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Papers by Robert Dauchy

Research paper thumbnail of Light: An Extrinsic Factor Influencing Animal-based Research

Journal of The American Association for Laboratory Animal Science, Dec 31, 2023

Research paper thumbnail of Identification ofanNAD(P)+-Dependent 'Malic' Enzyme inSmall-Intestinal -Mucosal Mitochondria

Research paper thumbnail of S04-2 Adaptability and Individual Difference in Melatonin Suppression by Light(Proceedings of The 8th International Congress of Physiological Anthropology)

Journal of Physiological Anthropology, Mar 1, 2007

Research paper thumbnail of A Method for Perfusion of Tissue-Isolated Human Tumor Xenografts in Nude Rats to Investigate the Oncostatic Role of the Physiological Nocturnal Melatonin Signal

Research paper thumbnail of Oral melatonin supplementation in rats and a human subject suppresses the growth activity of steroid receptor negative human breast cancer xenografts in female nude rats via an MT1 receptor-mediated suppression of signal tranduction and linoleic acid uptake and metabolism

Cancer Research, May 1, 2005

5776 The nocturnal circadian production of melatonin by the pineal gland provides an anticancer s... more 5776 The nocturnal circadian production of melatonin by the pineal gland provides an anticancer signal to tissue-isolated rat hepatoma 7288CTC. Melatonin’s anticancer mechanism involves a melatonin receptor-mediated reduction in cAMP formation resulting in an inhibition of linoleic acid (LA) uptake and its metabolism to mitogenically active 13-hydroxyoctadecadienoic acid (13-HODE); 13-HODE up-regulates the activity of the epidermal growth factor receptor/ MEK/ ERK1/2 growth pathway. Very little is known about melatonin’s anticancer effects on human breast cancer growth in vivo. We tested the effects of oral melatonin supplementation in both rats and a human subject on signal transduction activity, LA uptake/metabolism and growth activity in tissue-isolated, steroid receptor (SR) negative MCF-7 human breast cancer xenografts in female nude rats. These rats are nocturnally active and consume 90% of their food and water during the dark phase of a light/dark cycle (lights on 0600 - 1800 hrs). In study 1, beginning 2 wks prior to tumor implantation and continuing until the end of the study, groups of rats were given free access to drinking water to which melatonin and/or melatonin receptor antagonists were added. Rats consumed melatonin (5 μg/day) and receptor antagonists (10 μg/day), S20928 (MT1 receptors; Servier) or 4P-PDOT (MT2 receptors), either alone or in combination with melatonin. Tumor xenografts completely failed to develop in rats ingesting melatonin, either alone or in combination with 4P-PDOT. In contrast, melatonin suppression of tumor growth was completely blocked by S20928. Tumor growth activity, LA uptake, 13-HODE formation and cAMP levels were significantly higher in rats ingesting S20928, either alone or in combination with melatonin, than in controls; neither MEK nor ERK1/2 activation was affected. In study 2, (SR-) human breast cancer xenografts were perfused in situ for 1 hr with donor whole-blood collected during midday from an adult human volunteer just before and 1 hr after the oral ingestion of a commercial melatonin supplement (3 mg). Following oral melatonin intake, serum melatonin levels were increased by 75-fold and perfusion of tumors with melatonin-rich whole-blood resulted in a 70% decrease in tumor [3H]thymidine incorporation into DNA, and near total suppression of tumor cAMP levels, LA uptake/13-HODE formation, and MEK/ERK1/2 activation. These are the first results to demonstrate that oral melatonin supplementation, in rats and a human subject, prevented the proliferative activity of tissue-isolated (SR-) human breast cancer xenografts via a suppression of tumor signal transduction activity and LA uptake/13-HODE formation exclusively through an MT1 melatonin receptor-mediated mechanism.

Research paper thumbnail of Development and Characterization of a Novel Congenic Rat Strain for Obesity and Cancer Research

Nutrition and Cancer, Jan 9, 2018

The association between a Western Diet and colon cancer suggests that dietary factors and/or obes... more The association between a Western Diet and colon cancer suggests that dietary factors and/or obesity may contribute to cancer progression. Our objective was to develop a new animal model of obesity and the associated pathophysiology to investigate human cancer independent of dietary components that induce obesity. A novel congenic rat strain was established by introducing the fa allele from the Zucker rat into the Rowett Nude rat to generate a "fatty nude rat". The obese phenotype was first characterized in the new model. To then examine the utility of this model, lean and obese rats were implanted with HT-29 human colon cancer xenografts and tumor growth monitored. Fatty nude rats were visibly obese and did not develop fasting hyperglycemia. Compared to lean rats, fatty nude rats developed fasting hyperinsulinemia, glucose intolerance, and insulin resistance. Colon cancer tumor growth rate and final weight were increased (P < 0.05) in fatty nude compared to lean rats. Final tumor weight was associated with p38 kinase phosphorylation (P < 0.01) in fatty nude rats. We have established a novel model of obesity and pre-type 2 diabetes that can be used to investigate human cancer and therapeutics in the context of obesity and its associated pathophysiology.

Research paper thumbnail of Stimulation of tumor growth in adult rats in vivo during an acute fast

PubMed, Jul 1, 1986

These experiments investigate an increase in tumor growth that occurs in adult rats in vivo durin... more These experiments investigate an increase in tumor growth that occurs in adult rats in vivo during an acute fast. The effects of feeding, fasting, and underfeeding on the growth of Morris hepatomas 5123C and 7288CTC in Buffalo rats and of Walker carcinoma 256 and Jensen sarcoma in Sprague-Dawley rats were studied. Animals were matched for tumor size and growth during a period of ad libitum feeding preceding the fasting or underfeeding. Tumor growth was documented by increased size and incorporation of [methyl-3H]thymidine into tumor DNA. Fasting increased the rate of growth of the tumors 3 to 4 times over that measured in fed rats. This effect began during the first day of fasting and ended abruptly on refeeding. After refeeding tumor growth slowed to the rate in fed rats. Tumors from fed or fasted rats were not different in cellularity or dry weight/g wet weight. A positive growth response in the tumor required lipolysis and ketosis in the host. No stimulation was observed during an acute fast in either immature rats or in mature rats whose weights had been reduced by underfeeding. These animals have small fat stores and show no increase in arterial blood free fatty acid or ketone body concentrations during an acute fast. Finally, underfeeding of adult rats raised the blood concentrations of these nutrients to values that were intermediate between those in fasted and fed rats. Tumor growth rates in these rats were intermediate between those in fasted and fed rats. The results support the proposal that an increase in availability of free fatty acids and/or ketone bodies is the stimulus that increases the rate of tumor growth during an acute fast.

Research paper thumbnail of Epigenetic inhibition of the tumor suppressor ARHI by light at night‐induced circadian melatonin disruption mediates STAT3‐driven paclitaxel resistance in breast cancer

Journal of Pineal Research, Jun 9, 2019

Disruption of circadian time structure and suppression of circadian nocturnal melatonin (MLT) pro... more Disruption of circadian time structure and suppression of circadian nocturnal melatonin (MLT) production by exposure to dim light at night (dLAN), as occurs with night shift work and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of breast cancer and resistance to tamoxifen and doxorubicin. Melatonin inhibition of human breast cancer chemo-resistance involves mechanisms including suppression of tumor metabolism and inhibition of kinases and transcription factors which are often activated in drug-resistant breast cancer. Signal Transducer and Activator of Transcription 3 (STAT3), frequently overexpressed and activated in Paclitaxel (PTX)-resistant breast cancer, promotes the expression of DNA methyltransferase one (DNMT1) to epigenetically suppresses the transcription of tumor suppressor Aplasia Ras homolog one (ARHI) which can sequester STAT3 in the cytoplasm to block PTX-resistance. We demonstrate that breast tumor xenografts in rats exposed to dLAN and circadian MLT disrupted express elevated levels of phosphorylated and acetylated STAT3, increased DNMT1, but reduced Sirtuin 1 (SIRT1) and ARHI. Furthermore, MLT and/or SIRT1 administration blocked/reversed Interleukin 6 (IL-6)-induced acetylation of STAT3 and its methylation of ARH1 to increase ARH1 mRNA expression in MCF-7 breast cancer cells. Finally, analyses of the I-SPY 1 trial demonstrates that elevated MT1 receptor expression is significantly correlated with pathologic complete response following neo-adjuvant therapy in breast cancer patients. This is the first study to demonstrate circadian disruption of MLT by dLAN driving intrinsic resistance to PTX via epigenetic mechanisms increasing STAT3 expression and that MLT administration can reestablish sensitivity of breast tumors to PTX and drive tumor regression.

Research paper thumbnail of Abstract 36: Light exposure at night influences host/cancer circadian regulatory dynamics, Warburg effect, and human prostate cancer progression in nude rats

Current evidence indicates that rotating night shift workers have an increased risk of developing... more Current evidence indicates that rotating night shift workers have an increased risk of developing breast and prostate cancers, which have been associated with light at night (LAN)-induced circadian disruption as the principal risk factor. Previously, we demonstrated that animal room dark phase light contamination with as little as 0.20 lux (0.08 μW/cm2) suppressed the nocturnal production of the circadian oncostatic neurohormone melatonin and stimulated human breast tumor growth and metabolism. The circadian melatonin signal suppresses tumor growth and metabolism via an MT1 melatonin receptor-mediated signaling mechanism involving inhibition of aerobic glycolysis (Warburg effect) and linoleic acid (LA) uptake and conversion to the mitogen 13-hydroxyoctadecadienoic acid (13-HODE) culminating in down-regulation of the epidermal growth factor and insulin-like growth factor-1 pathways. We developed a new tissue-isolated androgen-receptor positive (AR+), castration-sensitive VCaP prostate tumor model in adult male athymic nude rats (Crl:NIH-Foxn1rnu), to test the hypothesis that nocturnal melatonin levels inhibit, while dim LAN (dLAN)-induced suppression of nocturnal melatonin production stimulates, tumor signaling, metabolic and growth activity. VCaP xenograft-bearing rats (n = 6/group) maintained on either a control light/dark cycle (LD, 12:12; 300 lux light phase intensity) or an experimental light/dark cycle (LD, 12:12dLAN (0.2 lux; dark phase intensity) for 6 weeks resulted in a 2.5-fold decrease in latency-to-onset (time of implant to first palpable mass) and 2-fold increase in tumor growth rates in experimental animals lacking a nocturnal circadian melatonin signal as compared to control animals with an intact melatonin signal. In control animals, plasma melatonin levels were high in the mid-dark phase (183.4 ± 12.8 pg/mL) and low (2.2 ± 0.4 pg/mL) in mid-light phase, while they were low throughout the 24-hr period in dLAN-exposed animals. Tumors harvested during the mid-dark phase (2400 h) revealed that cAMP levels, Warburg effect (increased glucose uptake and lactate production), LA uptake, 13-HODE production, and DNA [3H]Thymidine incorporation were all significantly elevated (P < 0.001) in dLAN as compared with the controls. Signaling pathways AKT, MEK, ERK ½, STAT3, GSK3ß, and NFκß were all phospho-activated along with increased expression of Aldo-keto reductase family 1 member C3 (AKR1C3) under dLAN conditions. AKR1C3 has been associated with intratumoral androgen synthesis and the development of castration-resistance. These findings are the first to show that the nocturnal melatonin signal inhibits, while dLAN stimulates the Warburg effect, LA metabolism and growth activity, signaling activity and AKR1C3 expression in VCaP human androgen-sensitive prostate cancer. Citation Format: Robert T. Dauchy, Melissa A. Wren, Erin M. Dauchy, Steven M. Hill, Lin Yuan, Shulin Xiang, Yan Dong, Victoria P. Belancio, David M. Blask. Light exposure at night influences host/cancer circadian regulatory dynamics, Warburg effect, and human prostate cancer progression in nude rats. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 36.

Research paper thumbnail of Anticancer Effects of Melatonin and Omega-3 Fatty Acids on Inhibition of Fatty Acid Transport in Human Cancer Xenograft-Bearing Nude Rats Occur via Receptor-Mediated Signal Transduction

Cancer Research, May 1, 2007

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4478 Melatonin (MLT), the pineal neurohorm... more AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4478 Melatonin (MLT), the pineal neurohormone secreted primarily at night in mammals, and omega-3 fatty acids (FAs) regulate linoleic acid (LA)-dependent growth in several rodent and human tumors in vivo . In tissue-isolated hepatoma 7288CTC and human MCF-7 steroid responsive and non-responsive tumors perfused in situ with arterial blood, MLT and eicosapentaenoic acid (EPA, omega-3 FA) inhibit LA-uptake and conversion to 13-hydroxyoctadecadienoic acid (13-HODE), a lipoxygenase product that stimulates EGF mitogenesis. The present study explores the effects of dietary intake of MLT (50 μg/day)/fish oil (5% FO) diet have on the growth and metabolism of tissue-isolated human PC3 prostate and FaDu hypopharyngeal squamous cell xenografts in nude rats. Control PC3 and FaDu tumor-bearing rats, raised on 5 % corn oil (CO) diet revealed tumor latency-to-onset and growth rates, respectively, of 18 and 26 days and 0.61 ± 0.08 and 0.46 ± 0.46 ± 0.06 g/day; final mean tumor weights were 6.2 ± 0.7 (PC3) and 6.0 ± 0.6 g (FaDu), respectively. LA uptake and 13-HODE release by PC3 and FaDu tumors were 7.9 ± 3.2 and 8.1 ± 2.4 μg/min/g, and 20.4 ± 3.8 and 18.5 ± 0.9 nmol/min/g, respectively. Incorporation of 3H-thymidine and DNA content for the PC3 and FaDu xenografts were 51.0 ± 4.9 and 61.6 ± 5.5 dpms/μg DNA, respectively, and 2.6 ± 0.2 and 4.0 ± 0.07 μg/g tumor. No tumors grew in animals raised on 5% FO/MLT diet. PC3 and FaDu tumors perfused in situ with donor animal blood augmented with either 1nM MLT or 0.4 mM EPA (plasma concentration) showed a complete inhibition of LA uptake, 13-HODE release, Erk 1/2 and MEK activities, and over a 50% reduction in tumor cAMP levels and [3H]thymidine incorporation into tumor DNA. The mean values for pH, PO2, and PCO2, between control and treatment regimens in arterial blood were 7.44 ± 0.02, 155 ± 18, and 32 ± 3, and 7.31 ± 0.03, 33 ± 4, and 57 ± 4 in the tumor venous blood, respectively. The inhibitions occurred via a Gi protein-coupled, cAMP-dependent signal trandsuction pathway and were reversed by forskolin, 8-Br-cAMP, and pertussis toxin.Furthermore, addition of 13-HODE reversed the inhibition of [3H]thymidine incorporation but had no effect on FA uptake. The Western diet contains an overabundance of LA and low amounts of both omega-3 FAs and MLT. Thus, understanding the underlying mechanism of action of these tumor growth-inhibitory agents will strengthen efforts to reduce LA and increase omega-3 and MLT consumption as a new cancer prevention strategy in humans.

Research paper thumbnail of Vivarium Lighting as an Important Extrinsic Factor Influencing Animal-based Research

Journal of The American Association for Laboratory Animal Science, 2023

Light is an extrinsic factor that exerts widespread influence on the regulation of circadian, phy... more Light is an extrinsic factor that exerts widespread influence on the regulation of circadian, physiologic, hormonal, ­metabolic, and behavioral systems of all animals, including those used in research. These wide-ranging biologic effects of light are ­mediated by distinct photoreceptors, the melanopsin-containing intrinsically photosensitive retinal ganglion cells of the nonvisual system, which interact with the rods and cones of the conventional visual system. Here, we review the nature of light and circadian rhythms, current industry practices and standards, and our present understanding of the neurophysiology of the visual and nonvisual systems. We also consider the implications of this extrinsic factor for vivarium measurement, production, and technological application of light, and provide simple recommendations on artificial lighting for use by regulatory authorities, lighting manufacturers, designers, engineers, researchers, and research animal care staff that ensure best practices for optimizing animal health and wellbeing and, ultimately, improving scientific outcomes.

Research paper thumbnail of Supplementary Figure 1 from Light at Night Activates IGF-1R/PDK1 Signaling and Accelerates Tumor Growth in Human Breast Cancer Xenografts

Supplemental Figure 1. PDK1 expression in tumors from control and PDK1 knockdown MCF7 SR-xenograf... more Supplemental Figure 1. PDK1 expression in tumors from control and PDK1 knockdown MCF7 SR-xenografts. Stable control luciferase (Luc) and PDK1 knockdown MCF-7 SR-cell lines were implanted in nude mice as described in the Materials and Methods. Immunoblotting analysis of PDK1, phospho-PDK1 Ser256 (pPDK1), and α-tubulin expression.

Research paper thumbnail of Data from Light at Night Activates IGF-1R/PDK1 Signaling and Accelerates Tumor Growth in Human Breast Cancer Xenografts

Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, in... more Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, including humans. However, the molecular mechanisms by which diurnal and circadian rhythms regulate cell proliferation are relatively poorly understood. In this study, we report that tumor growth in nude rats bearing human steroid receptor-negative MCF-7 breast tumors can be significantly accelerated by exposing the rats to light at night (LAN). Under normal conditions of an alternating light/dark cycle, proliferating cell nuclear antigen (PCNA) levels in tumors were maximal in the early light phase but remained at very low levels throughout the daily 24-hour cycle period monitored. Surprisingly, PCNA was expressed in tumors continually at a high level throughout the entire 24-hour period in LAN-exposed nude rats. Daily fluctuations of Akt and mitogen activated protein kinase activation in tumors were also disrupted by LAN. These fluctuations did not track with PCNA changes, but we found that activation of the Akt stimulatory kinase phosphoinositide-dependent protein kinase 1 (PDK1) directly correlated with PCNA levels. Expression of insulin-like growth factor 1 receptor (IGF-1R), an upstream signaling molecule for PDK1, also correlated with fluctuations of PDK1/PCNA in the LAN group. In addition, circulating IGF-1 concentrations were elevated in LAN-exposed tumor-bearing nude rats. Finally, RNAi-mediated knockdown of PDK1 led to a reduction in PCNA expression and cell proliferation in vitro and tumor growth in vivo, indicating that PDK1 regulates breast cancer growth in a manner correlated with PCNA expression. Taken together, our findings demonstrate that LAN exposure can accelerate tumor growth in vivo, in part through continuous activation of IGF-1R/PDK1 signaling. Cancer Res; 71(7); 2622–31. ©2011 AACR.

Research paper thumbnail of A Method for Growing Tissue-Isolated Human Tumor Xenografts in Nude Rats for Melatonin/Cancer Studies

Research paper thumbnail of Abstract 222: Exposure to dim light at night disrupts the nocturnal melatonin signal in male nude rats bearing tissue-isolated castration-sensitive VCaP human prostate cancer: Impact on tumor circadian dynamics of the Warburg effect, lipid signaling and proliferation

Cancer Research, Jun 15, 2022

Over 248,000 men in the U.S. alone this year will be diagnosed with prostate cancer, and over 33,... more Over 248,000 men in the U.S. alone this year will be diagnosed with prostate cancer, and over 33,300 will die from the disease. The World Health Organization, in the case of breast cancer, has classified night-shift work involving light at night (LAN)-induced circadian disruption to be a probable carcinogen (Class 2A). Exposure to LAN suppresses nighttime pineal melatonin (MLT) production that influences normal and neoplastic tissue metabolism, physiology, and proliferation. Previously, we showed in rodent and human tumors in vivo that MLT inhibits linoleic acid (LA)-uptake and conversion to 13-hydroxyoctadecadienoic acid (13-HODE), a lipoxygenase product that enhances epidermal growth factor and insulin-like growth factor-I-induced mitogenesis. Recently, we developed a tissue-isolated, castration-sensitive VCaP human prostate cancer xenograft model to test the hypothesis that suppression of the nocturnal MLT signal due to exposure to dim LAN (dLAN) accelerates tumor LA-uptake and metabolism, aerobic glycolysis (Warburg Effect), and proliferative activity. Male nude rats (Crl:NIHFoxn1rnu; n=6/group) bearing castration-sensitive VCaP human prostate cancer xenografts were maintained on either a control L(300 lux)D(0 lux),12:12 or experimental LD,12:12dLAN (300 lux light phase followed by dLAN 0.2 lux dark phase intensity) light/dark cycle. Results revealed (Mean ± S.D.) plasma MLT levels in controls peaked in the mid-dark phase (183.4 ± 12.8 pg/mL) and were lowest (2.2 ± 0.4 pg/mL) in the mid-light phase, and low (< 10 pg/mL) throughout the 24-hr period in dLAN rats. Tumors in rats exposed to dLAN exhibited a significantly shorter latency to onset and a two-fold faster growth rate than controls. Harvested control group tumors revealed elevated cAMP levels, LA uptake, 13-HODE production, the Warburg effect, and [3H]thymidine incorporation into DNA, as well as elevated patterns of expression of signaling pathways phospho-ERK1/2, -AKT, -STAT3, -glycogen synthase kinase-3β (GSK3β), and -NF-κβ, and full-length androgen receptor and aldo-keto reductase (AKR1C3), during the light phase and markedly suppressed during the dark phase. In the dLAN group, these measures were markedly elevated throughout the 24-hr period. This is the first evidence in vivo, that dLAN-induced disruption of integrated circadian rhythms of signaling, metabolism, and proliferation results in accelerated growth of castration-sensitive human prostate cancer xenografts. Thus, lighting design strategies to minimize human exposure to LAN that preserve the integrity of the circadian MLT signal may offer a novel approach to suppress the growth progression of human castration-sensitive prostate cancer in our increasingly 24-hour society. Citation Format: Erin M. Dauchy, Robert T. Dauchy, Steven M. Hill, Yan Dong, Victoria P. Belancio, Shulin Xiang, George C. Brainard, John P. Hanifin, David E. Blask. Exposure to dim light at night disrupts the nocturnal melatonin signal in male nude rats bearing tissue-isolated castration-sensitive VCaP human prostate cancer: Impact on tumor circadian dynamics of the Warburg effect, lipid signaling and proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 222.

Research paper thumbnail of Effects of Daytime Blue-Enriched LED Light on Physiologic Parameters of Three Common Mouse Strains Maintained on an IVC System

Journal of the American Association for Laboratory Animal Science

Light has been a crucial part of everyday life since the beginning of time. Most recently, light-... more Light has been a crucial part of everyday life since the beginning of time. Most recently, light-emitting diode (LED) light enriched in the blue-appearing portion of the visible spectrum (465 to 485 nm), which is more efficient in energy use, is becoming the normal lighting technology in facilities around the world. Previous reports revealed that blue-enriched LED light at day (bLAD) enhances animal health and wellbeing as compared with cool white fluorescent (CWF) lighting. We hypothesized that bLAD, compared with CWF light, has a positive influence on basic physiologic indices such as food consumption, water consumption, weight gain, nesting behavior, complete blood count, and blood chemistry profile. To test this, we allocated 360 mice into equal-sized groups by sex, strain (C3H/HeNCrl, C57BL/6NCrl, BALB/cAnNCrl), lighting conditions, and 6 blood collection time points (n = 5 mice/sex/strain/lighting condition/time point). Food consumption, water consumption, body weight, nest lo...

Research paper thumbnail of Influence of Light Phase Exposure to LED Lighting on Circadian Levels of Neuroendocrine Hormones in Sprague-Dawley Rats

Journal of the American Association for Laboratory Animal Science

Light and lighting protocols of animal research facilities are critically important to the outcom... more Light and lighting protocols of animal research facilities are critically important to the outcomes of biomedical research that uses animals. Previous studies from our laboratory showed that the wavelength (color) of light in animal housing areas affects the nocturnal melatonin signal that temporally coordinates circadian rhythms in rodents. Here, we tested the hypothesis that exposure to LED light enriched in the blue-appearing portion (460-480 nm) of the visible spectrum during the light phase (bLAD) influences circadian concentrations of select neuroendocrine hormones in adolescent Sprague–Dawley rats. Male and female rats (4 to 5 wk old) were housed on a novel IVC system under a 12L:12D in either cool-white fluorescent (control, n = 72) or bLAD (experimental, n = 72) lighting. Every third day, body weight and food and water consumption were measured. On Day 30, rats were anesthetized with ketamine/xylazine and terminal collection of arterial blood was performed to quantify serum...

Research paper thumbnail of Mitochondrial malic enzymes. Mitochondrial NAD(P)+-dependent malic enzyme activity and malate-dependent pyruvate formation are progression-linked in Morris hepatomas

Journal of Biological Chemistry, 1980

Fast-growing, undifferentiated tumors utilize glutamine as a major respiratory fuel (Kovacevic, Z... more Fast-growing, undifferentiated tumors utilize glutamine as a major respiratory fuel (Kovacevic, Z., and

Research paper thumbnail of Retinoic Acid-Related Orphan Receptor alpha 1 (RORα1) Induction of AKR1C3 Promotes MCF-7 Breast Cancer Cell Proliferation and Tamoxifen-Resistance which is Suppressed by Melatonin

Melatonin Research, 2020

The retinoic acid-related orphan receptors alpha (RORa) are members of the steroid/thyroid nuclea... more The retinoic acid-related orphan receptors alpha (RORa) are members of the steroid/thyroid nuclear receptor super-family and core components of the circadian timing system. In the present study, we continue to investigate the role of RORas in human breast cancer. Assays using the RORa response element (RORE)-tk-luciferase reporter demonstrate the functionality of the RORa1 in MCF-7 breast cancer cells and that over-expression of RORa1 stimulates MCF-7 human breast cancer cell proliferation. Genomic analysis revealed that RORα1 over-expression regulated the transcription of numerous genes in MCF-7 breast cancer cells including increasing the expression of connexin 43 (CX43), aldo-keto reductases 1C1 (AKR1C1), and AKR1C3. Furthermore, administration of the pineal hormone melatonin represses RORa1 induction of CX43, AKR1C1, and AKR1C3 in MCF-7 cells. AKR1C3 has been reported to impact in intra-tumoral production of androgens and estrogens and thus, might promote Tamoxifen resistance ...

Research paper thumbnail of Abstract 3191: Daytime blue-enriched LED light-induced circadian amplification of the nighttime melatonin signal increases sorafenib sensitivity in human hepatocellular carcinoma via enhanced suppression of the Warburg effect

Cancer Research, 2017

Over 36,000 people in the United States will be diagnosed with hepatocellular carcinoma (HCC) in ... more Over 36,000 people in the United States will be diagnosed with hepatocellular carcinoma (HCC) in 2016, the second leading cause of cancer death worldwide. Metabolic pathways within the liver and in HCC are highly regulated by the central circadian clock in the suprachiastmatic nucleus (SCN). The SCN drives nighttime production of the circadian anti-cancer hormone melatonin by the pineal gland in rats and humans. We have shown that the nighttime circadian melatonin signal suppresses the Warburg effect (aerobic glycolysis) in human breast cancer xenografts and that blue-enriched light (460-480 nm) from LEDs at daytime (bLAD), amplifies the nighttime circadian melatonin signal by 7-fold in rats over cool white fluorescent (CWF) lighting. Here we tested whether daytime exposure of tissue-isolated HepG2 xenograft-bearing male nude rats to bLAD amplifies the nighttime melatonin signal to increase tumor sensitivity to nighttime administered sorafenib (FDA-approved multi-kinase inhibitor) t...

Research paper thumbnail of Light: An Extrinsic Factor Influencing Animal-based Research

Journal of The American Association for Laboratory Animal Science, Dec 31, 2023

Research paper thumbnail of Identification ofanNAD(P)+-Dependent 'Malic' Enzyme inSmall-Intestinal -Mucosal Mitochondria

Research paper thumbnail of S04-2 Adaptability and Individual Difference in Melatonin Suppression by Light(Proceedings of The 8th International Congress of Physiological Anthropology)

Journal of Physiological Anthropology, Mar 1, 2007

Research paper thumbnail of A Method for Perfusion of Tissue-Isolated Human Tumor Xenografts in Nude Rats to Investigate the Oncostatic Role of the Physiological Nocturnal Melatonin Signal

Research paper thumbnail of Oral melatonin supplementation in rats and a human subject suppresses the growth activity of steroid receptor negative human breast cancer xenografts in female nude rats via an MT1 receptor-mediated suppression of signal tranduction and linoleic acid uptake and metabolism

Cancer Research, May 1, 2005

5776 The nocturnal circadian production of melatonin by the pineal gland provides an anticancer s... more 5776 The nocturnal circadian production of melatonin by the pineal gland provides an anticancer signal to tissue-isolated rat hepatoma 7288CTC. Melatonin’s anticancer mechanism involves a melatonin receptor-mediated reduction in cAMP formation resulting in an inhibition of linoleic acid (LA) uptake and its metabolism to mitogenically active 13-hydroxyoctadecadienoic acid (13-HODE); 13-HODE up-regulates the activity of the epidermal growth factor receptor/ MEK/ ERK1/2 growth pathway. Very little is known about melatonin’s anticancer effects on human breast cancer growth in vivo. We tested the effects of oral melatonin supplementation in both rats and a human subject on signal transduction activity, LA uptake/metabolism and growth activity in tissue-isolated, steroid receptor (SR) negative MCF-7 human breast cancer xenografts in female nude rats. These rats are nocturnally active and consume 90% of their food and water during the dark phase of a light/dark cycle (lights on 0600 - 1800 hrs). In study 1, beginning 2 wks prior to tumor implantation and continuing until the end of the study, groups of rats were given free access to drinking water to which melatonin and/or melatonin receptor antagonists were added. Rats consumed melatonin (5 μg/day) and receptor antagonists (10 μg/day), S20928 (MT1 receptors; Servier) or 4P-PDOT (MT2 receptors), either alone or in combination with melatonin. Tumor xenografts completely failed to develop in rats ingesting melatonin, either alone or in combination with 4P-PDOT. In contrast, melatonin suppression of tumor growth was completely blocked by S20928. Tumor growth activity, LA uptake, 13-HODE formation and cAMP levels were significantly higher in rats ingesting S20928, either alone or in combination with melatonin, than in controls; neither MEK nor ERK1/2 activation was affected. In study 2, (SR-) human breast cancer xenografts were perfused in situ for 1 hr with donor whole-blood collected during midday from an adult human volunteer just before and 1 hr after the oral ingestion of a commercial melatonin supplement (3 mg). Following oral melatonin intake, serum melatonin levels were increased by 75-fold and perfusion of tumors with melatonin-rich whole-blood resulted in a 70% decrease in tumor [3H]thymidine incorporation into DNA, and near total suppression of tumor cAMP levels, LA uptake/13-HODE formation, and MEK/ERK1/2 activation. These are the first results to demonstrate that oral melatonin supplementation, in rats and a human subject, prevented the proliferative activity of tissue-isolated (SR-) human breast cancer xenografts via a suppression of tumor signal transduction activity and LA uptake/13-HODE formation exclusively through an MT1 melatonin receptor-mediated mechanism.

Research paper thumbnail of Development and Characterization of a Novel Congenic Rat Strain for Obesity and Cancer Research

Nutrition and Cancer, Jan 9, 2018

The association between a Western Diet and colon cancer suggests that dietary factors and/or obes... more The association between a Western Diet and colon cancer suggests that dietary factors and/or obesity may contribute to cancer progression. Our objective was to develop a new animal model of obesity and the associated pathophysiology to investigate human cancer independent of dietary components that induce obesity. A novel congenic rat strain was established by introducing the fa allele from the Zucker rat into the Rowett Nude rat to generate a "fatty nude rat". The obese phenotype was first characterized in the new model. To then examine the utility of this model, lean and obese rats were implanted with HT-29 human colon cancer xenografts and tumor growth monitored. Fatty nude rats were visibly obese and did not develop fasting hyperglycemia. Compared to lean rats, fatty nude rats developed fasting hyperinsulinemia, glucose intolerance, and insulin resistance. Colon cancer tumor growth rate and final weight were increased (P < 0.05) in fatty nude compared to lean rats. Final tumor weight was associated with p38 kinase phosphorylation (P < 0.01) in fatty nude rats. We have established a novel model of obesity and pre-type 2 diabetes that can be used to investigate human cancer and therapeutics in the context of obesity and its associated pathophysiology.

Research paper thumbnail of Stimulation of tumor growth in adult rats in vivo during an acute fast

PubMed, Jul 1, 1986

These experiments investigate an increase in tumor growth that occurs in adult rats in vivo durin... more These experiments investigate an increase in tumor growth that occurs in adult rats in vivo during an acute fast. The effects of feeding, fasting, and underfeeding on the growth of Morris hepatomas 5123C and 7288CTC in Buffalo rats and of Walker carcinoma 256 and Jensen sarcoma in Sprague-Dawley rats were studied. Animals were matched for tumor size and growth during a period of ad libitum feeding preceding the fasting or underfeeding. Tumor growth was documented by increased size and incorporation of [methyl-3H]thymidine into tumor DNA. Fasting increased the rate of growth of the tumors 3 to 4 times over that measured in fed rats. This effect began during the first day of fasting and ended abruptly on refeeding. After refeeding tumor growth slowed to the rate in fed rats. Tumors from fed or fasted rats were not different in cellularity or dry weight/g wet weight. A positive growth response in the tumor required lipolysis and ketosis in the host. No stimulation was observed during an acute fast in either immature rats or in mature rats whose weights had been reduced by underfeeding. These animals have small fat stores and show no increase in arterial blood free fatty acid or ketone body concentrations during an acute fast. Finally, underfeeding of adult rats raised the blood concentrations of these nutrients to values that were intermediate between those in fasted and fed rats. Tumor growth rates in these rats were intermediate between those in fasted and fed rats. The results support the proposal that an increase in availability of free fatty acids and/or ketone bodies is the stimulus that increases the rate of tumor growth during an acute fast.

Research paper thumbnail of Epigenetic inhibition of the tumor suppressor ARHI by light at night‐induced circadian melatonin disruption mediates STAT3‐driven paclitaxel resistance in breast cancer

Journal of Pineal Research, Jun 9, 2019

Disruption of circadian time structure and suppression of circadian nocturnal melatonin (MLT) pro... more Disruption of circadian time structure and suppression of circadian nocturnal melatonin (MLT) production by exposure to dim light at night (dLAN), as occurs with night shift work and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of breast cancer and resistance to tamoxifen and doxorubicin. Melatonin inhibition of human breast cancer chemo-resistance involves mechanisms including suppression of tumor metabolism and inhibition of kinases and transcription factors which are often activated in drug-resistant breast cancer. Signal Transducer and Activator of Transcription 3 (STAT3), frequently overexpressed and activated in Paclitaxel (PTX)-resistant breast cancer, promotes the expression of DNA methyltransferase one (DNMT1) to epigenetically suppresses the transcription of tumor suppressor Aplasia Ras homolog one (ARHI) which can sequester STAT3 in the cytoplasm to block PTX-resistance. We demonstrate that breast tumor xenografts in rats exposed to dLAN and circadian MLT disrupted express elevated levels of phosphorylated and acetylated STAT3, increased DNMT1, but reduced Sirtuin 1 (SIRT1) and ARHI. Furthermore, MLT and/or SIRT1 administration blocked/reversed Interleukin 6 (IL-6)-induced acetylation of STAT3 and its methylation of ARH1 to increase ARH1 mRNA expression in MCF-7 breast cancer cells. Finally, analyses of the I-SPY 1 trial demonstrates that elevated MT1 receptor expression is significantly correlated with pathologic complete response following neo-adjuvant therapy in breast cancer patients. This is the first study to demonstrate circadian disruption of MLT by dLAN driving intrinsic resistance to PTX via epigenetic mechanisms increasing STAT3 expression and that MLT administration can reestablish sensitivity of breast tumors to PTX and drive tumor regression.

Research paper thumbnail of Abstract 36: Light exposure at night influences host/cancer circadian regulatory dynamics, Warburg effect, and human prostate cancer progression in nude rats

Current evidence indicates that rotating night shift workers have an increased risk of developing... more Current evidence indicates that rotating night shift workers have an increased risk of developing breast and prostate cancers, which have been associated with light at night (LAN)-induced circadian disruption as the principal risk factor. Previously, we demonstrated that animal room dark phase light contamination with as little as 0.20 lux (0.08 μW/cm2) suppressed the nocturnal production of the circadian oncostatic neurohormone melatonin and stimulated human breast tumor growth and metabolism. The circadian melatonin signal suppresses tumor growth and metabolism via an MT1 melatonin receptor-mediated signaling mechanism involving inhibition of aerobic glycolysis (Warburg effect) and linoleic acid (LA) uptake and conversion to the mitogen 13-hydroxyoctadecadienoic acid (13-HODE) culminating in down-regulation of the epidermal growth factor and insulin-like growth factor-1 pathways. We developed a new tissue-isolated androgen-receptor positive (AR+), castration-sensitive VCaP prostate tumor model in adult male athymic nude rats (Crl:NIH-Foxn1rnu), to test the hypothesis that nocturnal melatonin levels inhibit, while dim LAN (dLAN)-induced suppression of nocturnal melatonin production stimulates, tumor signaling, metabolic and growth activity. VCaP xenograft-bearing rats (n = 6/group) maintained on either a control light/dark cycle (LD, 12:12; 300 lux light phase intensity) or an experimental light/dark cycle (LD, 12:12dLAN (0.2 lux; dark phase intensity) for 6 weeks resulted in a 2.5-fold decrease in latency-to-onset (time of implant to first palpable mass) and 2-fold increase in tumor growth rates in experimental animals lacking a nocturnal circadian melatonin signal as compared to control animals with an intact melatonin signal. In control animals, plasma melatonin levels were high in the mid-dark phase (183.4 ± 12.8 pg/mL) and low (2.2 ± 0.4 pg/mL) in mid-light phase, while they were low throughout the 24-hr period in dLAN-exposed animals. Tumors harvested during the mid-dark phase (2400 h) revealed that cAMP levels, Warburg effect (increased glucose uptake and lactate production), LA uptake, 13-HODE production, and DNA [3H]Thymidine incorporation were all significantly elevated (P < 0.001) in dLAN as compared with the controls. Signaling pathways AKT, MEK, ERK ½, STAT3, GSK3ß, and NFκß were all phospho-activated along with increased expression of Aldo-keto reductase family 1 member C3 (AKR1C3) under dLAN conditions. AKR1C3 has been associated with intratumoral androgen synthesis and the development of castration-resistance. These findings are the first to show that the nocturnal melatonin signal inhibits, while dLAN stimulates the Warburg effect, LA metabolism and growth activity, signaling activity and AKR1C3 expression in VCaP human androgen-sensitive prostate cancer. Citation Format: Robert T. Dauchy, Melissa A. Wren, Erin M. Dauchy, Steven M. Hill, Lin Yuan, Shulin Xiang, Yan Dong, Victoria P. Belancio, David M. Blask. Light exposure at night influences host/cancer circadian regulatory dynamics, Warburg effect, and human prostate cancer progression in nude rats. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 36.

Research paper thumbnail of Anticancer Effects of Melatonin and Omega-3 Fatty Acids on Inhibition of Fatty Acid Transport in Human Cancer Xenograft-Bearing Nude Rats Occur via Receptor-Mediated Signal Transduction

Cancer Research, May 1, 2007

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4478 Melatonin (MLT), the pineal neurohorm... more AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4478 Melatonin (MLT), the pineal neurohormone secreted primarily at night in mammals, and omega-3 fatty acids (FAs) regulate linoleic acid (LA)-dependent growth in several rodent and human tumors in vivo . In tissue-isolated hepatoma 7288CTC and human MCF-7 steroid responsive and non-responsive tumors perfused in situ with arterial blood, MLT and eicosapentaenoic acid (EPA, omega-3 FA) inhibit LA-uptake and conversion to 13-hydroxyoctadecadienoic acid (13-HODE), a lipoxygenase product that stimulates EGF mitogenesis. The present study explores the effects of dietary intake of MLT (50 μg/day)/fish oil (5% FO) diet have on the growth and metabolism of tissue-isolated human PC3 prostate and FaDu hypopharyngeal squamous cell xenografts in nude rats. Control PC3 and FaDu tumor-bearing rats, raised on 5 % corn oil (CO) diet revealed tumor latency-to-onset and growth rates, respectively, of 18 and 26 days and 0.61 ± 0.08 and 0.46 ± 0.46 ± 0.06 g/day; final mean tumor weights were 6.2 ± 0.7 (PC3) and 6.0 ± 0.6 g (FaDu), respectively. LA uptake and 13-HODE release by PC3 and FaDu tumors were 7.9 ± 3.2 and 8.1 ± 2.4 μg/min/g, and 20.4 ± 3.8 and 18.5 ± 0.9 nmol/min/g, respectively. Incorporation of 3H-thymidine and DNA content for the PC3 and FaDu xenografts were 51.0 ± 4.9 and 61.6 ± 5.5 dpms/μg DNA, respectively, and 2.6 ± 0.2 and 4.0 ± 0.07 μg/g tumor. No tumors grew in animals raised on 5% FO/MLT diet. PC3 and FaDu tumors perfused in situ with donor animal blood augmented with either 1nM MLT or 0.4 mM EPA (plasma concentration) showed a complete inhibition of LA uptake, 13-HODE release, Erk 1/2 and MEK activities, and over a 50% reduction in tumor cAMP levels and [3H]thymidine incorporation into tumor DNA. The mean values for pH, PO2, and PCO2, between control and treatment regimens in arterial blood were 7.44 ± 0.02, 155 ± 18, and 32 ± 3, and 7.31 ± 0.03, 33 ± 4, and 57 ± 4 in the tumor venous blood, respectively. The inhibitions occurred via a Gi protein-coupled, cAMP-dependent signal trandsuction pathway and were reversed by forskolin, 8-Br-cAMP, and pertussis toxin.Furthermore, addition of 13-HODE reversed the inhibition of [3H]thymidine incorporation but had no effect on FA uptake. The Western diet contains an overabundance of LA and low amounts of both omega-3 FAs and MLT. Thus, understanding the underlying mechanism of action of these tumor growth-inhibitory agents will strengthen efforts to reduce LA and increase omega-3 and MLT consumption as a new cancer prevention strategy in humans.

Research paper thumbnail of Vivarium Lighting as an Important Extrinsic Factor Influencing Animal-based Research

Journal of The American Association for Laboratory Animal Science, 2023

Light is an extrinsic factor that exerts widespread influence on the regulation of circadian, phy... more Light is an extrinsic factor that exerts widespread influence on the regulation of circadian, physiologic, hormonal, ­metabolic, and behavioral systems of all animals, including those used in research. These wide-ranging biologic effects of light are ­mediated by distinct photoreceptors, the melanopsin-containing intrinsically photosensitive retinal ganglion cells of the nonvisual system, which interact with the rods and cones of the conventional visual system. Here, we review the nature of light and circadian rhythms, current industry practices and standards, and our present understanding of the neurophysiology of the visual and nonvisual systems. We also consider the implications of this extrinsic factor for vivarium measurement, production, and technological application of light, and provide simple recommendations on artificial lighting for use by regulatory authorities, lighting manufacturers, designers, engineers, researchers, and research animal care staff that ensure best practices for optimizing animal health and wellbeing and, ultimately, improving scientific outcomes.

Research paper thumbnail of Supplementary Figure 1 from Light at Night Activates IGF-1R/PDK1 Signaling and Accelerates Tumor Growth in Human Breast Cancer Xenografts

Supplemental Figure 1. PDK1 expression in tumors from control and PDK1 knockdown MCF7 SR-xenograf... more Supplemental Figure 1. PDK1 expression in tumors from control and PDK1 knockdown MCF7 SR-xenografts. Stable control luciferase (Luc) and PDK1 knockdown MCF-7 SR-cell lines were implanted in nude mice as described in the Materials and Methods. Immunoblotting analysis of PDK1, phospho-PDK1 Ser256 (pPDK1), and α-tubulin expression.

Research paper thumbnail of Data from Light at Night Activates IGF-1R/PDK1 Signaling and Accelerates Tumor Growth in Human Breast Cancer Xenografts

Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, in... more Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, including humans. However, the molecular mechanisms by which diurnal and circadian rhythms regulate cell proliferation are relatively poorly understood. In this study, we report that tumor growth in nude rats bearing human steroid receptor-negative MCF-7 breast tumors can be significantly accelerated by exposing the rats to light at night (LAN). Under normal conditions of an alternating light/dark cycle, proliferating cell nuclear antigen (PCNA) levels in tumors were maximal in the early light phase but remained at very low levels throughout the daily 24-hour cycle period monitored. Surprisingly, PCNA was expressed in tumors continually at a high level throughout the entire 24-hour period in LAN-exposed nude rats. Daily fluctuations of Akt and mitogen activated protein kinase activation in tumors were also disrupted by LAN. These fluctuations did not track with PCNA changes, but we found that activation of the Akt stimulatory kinase phosphoinositide-dependent protein kinase 1 (PDK1) directly correlated with PCNA levels. Expression of insulin-like growth factor 1 receptor (IGF-1R), an upstream signaling molecule for PDK1, also correlated with fluctuations of PDK1/PCNA in the LAN group. In addition, circulating IGF-1 concentrations were elevated in LAN-exposed tumor-bearing nude rats. Finally, RNAi-mediated knockdown of PDK1 led to a reduction in PCNA expression and cell proliferation in vitro and tumor growth in vivo, indicating that PDK1 regulates breast cancer growth in a manner correlated with PCNA expression. Taken together, our findings demonstrate that LAN exposure can accelerate tumor growth in vivo, in part through continuous activation of IGF-1R/PDK1 signaling. Cancer Res; 71(7); 2622–31. ©2011 AACR.

Research paper thumbnail of A Method for Growing Tissue-Isolated Human Tumor Xenografts in Nude Rats for Melatonin/Cancer Studies

Research paper thumbnail of Abstract 222: Exposure to dim light at night disrupts the nocturnal melatonin signal in male nude rats bearing tissue-isolated castration-sensitive VCaP human prostate cancer: Impact on tumor circadian dynamics of the Warburg effect, lipid signaling and proliferation

Cancer Research, Jun 15, 2022

Over 248,000 men in the U.S. alone this year will be diagnosed with prostate cancer, and over 33,... more Over 248,000 men in the U.S. alone this year will be diagnosed with prostate cancer, and over 33,300 will die from the disease. The World Health Organization, in the case of breast cancer, has classified night-shift work involving light at night (LAN)-induced circadian disruption to be a probable carcinogen (Class 2A). Exposure to LAN suppresses nighttime pineal melatonin (MLT) production that influences normal and neoplastic tissue metabolism, physiology, and proliferation. Previously, we showed in rodent and human tumors in vivo that MLT inhibits linoleic acid (LA)-uptake and conversion to 13-hydroxyoctadecadienoic acid (13-HODE), a lipoxygenase product that enhances epidermal growth factor and insulin-like growth factor-I-induced mitogenesis. Recently, we developed a tissue-isolated, castration-sensitive VCaP human prostate cancer xenograft model to test the hypothesis that suppression of the nocturnal MLT signal due to exposure to dim LAN (dLAN) accelerates tumor LA-uptake and metabolism, aerobic glycolysis (Warburg Effect), and proliferative activity. Male nude rats (Crl:NIHFoxn1rnu; n=6/group) bearing castration-sensitive VCaP human prostate cancer xenografts were maintained on either a control L(300 lux)D(0 lux),12:12 or experimental LD,12:12dLAN (300 lux light phase followed by dLAN 0.2 lux dark phase intensity) light/dark cycle. Results revealed (Mean ± S.D.) plasma MLT levels in controls peaked in the mid-dark phase (183.4 ± 12.8 pg/mL) and were lowest (2.2 ± 0.4 pg/mL) in the mid-light phase, and low (< 10 pg/mL) throughout the 24-hr period in dLAN rats. Tumors in rats exposed to dLAN exhibited a significantly shorter latency to onset and a two-fold faster growth rate than controls. Harvested control group tumors revealed elevated cAMP levels, LA uptake, 13-HODE production, the Warburg effect, and [3H]thymidine incorporation into DNA, as well as elevated patterns of expression of signaling pathways phospho-ERK1/2, -AKT, -STAT3, -glycogen synthase kinase-3β (GSK3β), and -NF-κβ, and full-length androgen receptor and aldo-keto reductase (AKR1C3), during the light phase and markedly suppressed during the dark phase. In the dLAN group, these measures were markedly elevated throughout the 24-hr period. This is the first evidence in vivo, that dLAN-induced disruption of integrated circadian rhythms of signaling, metabolism, and proliferation results in accelerated growth of castration-sensitive human prostate cancer xenografts. Thus, lighting design strategies to minimize human exposure to LAN that preserve the integrity of the circadian MLT signal may offer a novel approach to suppress the growth progression of human castration-sensitive prostate cancer in our increasingly 24-hour society. Citation Format: Erin M. Dauchy, Robert T. Dauchy, Steven M. Hill, Yan Dong, Victoria P. Belancio, Shulin Xiang, George C. Brainard, John P. Hanifin, David E. Blask. Exposure to dim light at night disrupts the nocturnal melatonin signal in male nude rats bearing tissue-isolated castration-sensitive VCaP human prostate cancer: Impact on tumor circadian dynamics of the Warburg effect, lipid signaling and proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 222.

Research paper thumbnail of Effects of Daytime Blue-Enriched LED Light on Physiologic Parameters of Three Common Mouse Strains Maintained on an IVC System

Journal of the American Association for Laboratory Animal Science

Light has been a crucial part of everyday life since the beginning of time. Most recently, light-... more Light has been a crucial part of everyday life since the beginning of time. Most recently, light-emitting diode (LED) light enriched in the blue-appearing portion of the visible spectrum (465 to 485 nm), which is more efficient in energy use, is becoming the normal lighting technology in facilities around the world. Previous reports revealed that blue-enriched LED light at day (bLAD) enhances animal health and wellbeing as compared with cool white fluorescent (CWF) lighting. We hypothesized that bLAD, compared with CWF light, has a positive influence on basic physiologic indices such as food consumption, water consumption, weight gain, nesting behavior, complete blood count, and blood chemistry profile. To test this, we allocated 360 mice into equal-sized groups by sex, strain (C3H/HeNCrl, C57BL/6NCrl, BALB/cAnNCrl), lighting conditions, and 6 blood collection time points (n = 5 mice/sex/strain/lighting condition/time point). Food consumption, water consumption, body weight, nest lo...

Research paper thumbnail of Influence of Light Phase Exposure to LED Lighting on Circadian Levels of Neuroendocrine Hormones in Sprague-Dawley Rats

Journal of the American Association for Laboratory Animal Science

Light and lighting protocols of animal research facilities are critically important to the outcom... more Light and lighting protocols of animal research facilities are critically important to the outcomes of biomedical research that uses animals. Previous studies from our laboratory showed that the wavelength (color) of light in animal housing areas affects the nocturnal melatonin signal that temporally coordinates circadian rhythms in rodents. Here, we tested the hypothesis that exposure to LED light enriched in the blue-appearing portion (460-480 nm) of the visible spectrum during the light phase (bLAD) influences circadian concentrations of select neuroendocrine hormones in adolescent Sprague–Dawley rats. Male and female rats (4 to 5 wk old) were housed on a novel IVC system under a 12L:12D in either cool-white fluorescent (control, n = 72) or bLAD (experimental, n = 72) lighting. Every third day, body weight and food and water consumption were measured. On Day 30, rats were anesthetized with ketamine/xylazine and terminal collection of arterial blood was performed to quantify serum...

Research paper thumbnail of Mitochondrial malic enzymes. Mitochondrial NAD(P)+-dependent malic enzyme activity and malate-dependent pyruvate formation are progression-linked in Morris hepatomas

Journal of Biological Chemistry, 1980

Fast-growing, undifferentiated tumors utilize glutamine as a major respiratory fuel (Kovacevic, Z... more Fast-growing, undifferentiated tumors utilize glutamine as a major respiratory fuel (Kovacevic, Z., and

Research paper thumbnail of Retinoic Acid-Related Orphan Receptor alpha 1 (RORα1) Induction of AKR1C3 Promotes MCF-7 Breast Cancer Cell Proliferation and Tamoxifen-Resistance which is Suppressed by Melatonin

Melatonin Research, 2020

The retinoic acid-related orphan receptors alpha (RORa) are members of the steroid/thyroid nuclea... more The retinoic acid-related orphan receptors alpha (RORa) are members of the steroid/thyroid nuclear receptor super-family and core components of the circadian timing system. In the present study, we continue to investigate the role of RORas in human breast cancer. Assays using the RORa response element (RORE)-tk-luciferase reporter demonstrate the functionality of the RORa1 in MCF-7 breast cancer cells and that over-expression of RORa1 stimulates MCF-7 human breast cancer cell proliferation. Genomic analysis revealed that RORα1 over-expression regulated the transcription of numerous genes in MCF-7 breast cancer cells including increasing the expression of connexin 43 (CX43), aldo-keto reductases 1C1 (AKR1C1), and AKR1C3. Furthermore, administration of the pineal hormone melatonin represses RORa1 induction of CX43, AKR1C1, and AKR1C3 in MCF-7 cells. AKR1C3 has been reported to impact in intra-tumoral production of androgens and estrogens and thus, might promote Tamoxifen resistance ...

Research paper thumbnail of Abstract 3191: Daytime blue-enriched LED light-induced circadian amplification of the nighttime melatonin signal increases sorafenib sensitivity in human hepatocellular carcinoma via enhanced suppression of the Warburg effect

Cancer Research, 2017

Over 36,000 people in the United States will be diagnosed with hepatocellular carcinoma (HCC) in ... more Over 36,000 people in the United States will be diagnosed with hepatocellular carcinoma (HCC) in 2016, the second leading cause of cancer death worldwide. Metabolic pathways within the liver and in HCC are highly regulated by the central circadian clock in the suprachiastmatic nucleus (SCN). The SCN drives nighttime production of the circadian anti-cancer hormone melatonin by the pineal gland in rats and humans. We have shown that the nighttime circadian melatonin signal suppresses the Warburg effect (aerobic glycolysis) in human breast cancer xenografts and that blue-enriched light (460-480 nm) from LEDs at daytime (bLAD), amplifies the nighttime circadian melatonin signal by 7-fold in rats over cool white fluorescent (CWF) lighting. Here we tested whether daytime exposure of tissue-isolated HepG2 xenograft-bearing male nude rats to bLAD amplifies the nighttime melatonin signal to increase tumor sensitivity to nighttime administered sorafenib (FDA-approved multi-kinase inhibitor) t...