Sharmistha Chakraborty - Academia.edu (original) (raw)

Papers by Sharmistha Chakraborty

Research paper thumbnail of An EGFR wild type–EGFRvIII–HB-EGF feed-forward loop regulates the activation of EGFRvIII

Research paper thumbnail of Targeting Glutamine Metabolism with a Novel Na+/K+-ATPase Inhibitor RX108 in Hepatocellular Carcinoma

Molecular Cancer Therapeutics, Feb 10, 2023

The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the ... more The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the most common form of liver cancer, highlight the urgent need to identify novel therapeutic modalities. Here, we describe the antitumor activity and underlying molecular mechanisms of a novel Na+/K+-ATPase inhibitor RX108 in human HCC cells and its xenograft model. RX108 dose-dependently inhibited HCC cell proliferation in vitro and tumor growth in a xenograft mouse model, and that the inhibition was associated with induction of apoptosis. Mechanistically, RX108 significantly downregulated alanine serine cysteine transporter 2 (ASCT2) protein expression and reduced glutamine and glutamate concentration in HCC cells and tumors. In addition, RX108 exposure led to a significant decrease in cell energy metabolism in Huh7 and Hep3B cells, including decreased levels of glutathione, NADH, NADPH, and mitochondrial respiration oxygen consumption rate. Furthermore, HCC cells exhibited evidence of glutamine addiction; the antiproliferative effect of RX108 was dependent on glutamine transport. Clinically, elevated ASCT2 mRNA expression in HCCs was associated with unfavorable survival. Taken together, these findings reveal a novel approach to target glutamine metabolism through inhibiting Na+/K+-ATPase and provide a rationale for using RX108 to treat HCC in patients whose tumors express ASCT2 at high levels. RX108 is currently under clinical development.

Research paper thumbnail of Figure S1-S5 from Targeting Glutamine Metabolism with a Novel Na+/K+-ATPase Inhibitor RX108 in Hepatocellular Carcinoma

Supplemental Figures S1-S5

Research paper thumbnail of Abstract 5075: PBI-05204, a supercritical CO2 extract of Nerium oleander, suppresses the stemness of glioblastoma stem cells and inhibits the Shh-Gli1-NANOG axis

Cancer Research

Glioblastoma multiforme (GBM) is an aggressive form of primary brain neoplasm that has a poor pro... more Glioblastoma multiforme (GBM) is an aggressive form of primary brain neoplasm that has a poor prognosis and is resistant to conventional treatment. There is a great need to develop new strategies to improve the outcome of this disease. PBI-05204, a supercritical CO2 Nerium oleander extract containing cardiac glycosides, such as oleandrin, has been tested in Phase I and II clinical trials for treatment of solid tumors. The purpose of the present study was to examine the efficacy of PBI-05204 against GBM and to explore potential mechanisms of action. Rapid growth of GBM has been associated with the presence of pluripotent cancer stem cells that have the capacity of self-renewal, proliferation, and formation of cancer progenitor cells. Genome wide expression profiling of Glioblastoma stem cells (GSCs) demonstrates similarities to embryonic stem cells (ESCs) and progenitor cells defining a pattern of hierarchical appearance of Embryonic stem cell markers: NANOG, SOX2, and GFAP. Using cu...

Research paper thumbnail of Abstract 5382: Biofield therapy suppressed the growth of human pancreatic cancer cells by modulation of cell cycle and cell voltage potentials

Cancer Research

Biofield therapies have gained popularity and are being explored as possible treatments for cance... more Biofield therapies have gained popularity and are being explored as possible treatments for cancer. In some cases, devices have been developed that mimic the electromagnetic fields (EMF) that are emitted from people delivering biofield therapies. However, it is not clear if EMFs are the mechanism of action. We previously reported that biofield therapy significantly inhibited the growth of lung cancer cells in vitro and their relevant animal model mediated through inflammatory and immune pathways. We expanded this research to examine the effects of human biofield therapy on the growth of pancreatic ductal adenocarcinoma (PDAC) cells and explored relevant mechanisms. Cell viability of human pancreatic cancer Panc-1 and mouse pancreatic cancer Panc02 cells was measured by PrestoBlue assay. Cell cycle was measured by PI staining and cell voltage potentials were assessed using DiBAC4 staining. It is well-established that cancer cells have distinct bioelectrical properties and most have d...

Research paper thumbnail of Abstract 5954: Dietary sugar promotes breast tumorigenesis partially through upregulating 12 lipoxygenase/PPARd signaling and remodeling breast tumor microenvironment

Cancer Research

Ample evidence from epidemiological studies links high-sugar diets with increased breast cancer r... more Ample evidence from epidemiological studies links high-sugar diets with increased breast cancer risk, but the underlying molecular mechanisms remain unclear. We previously reported that sucrose-enriched diets (SED) accelerated breast tumorigenesis in MMTV-ErbB2 mice and promoted the breast tumor growth in orthotopic models of mouse (4T1) or human breast cancer cells (MDA-MB-231) by up-regulating 12-lipoxygenase (12-LOX) and its arachidonate metabolite 12-HETE. In this report, we performed mechanistic studies to determine the role of 12-LOX in SED-induced breast tumorigenesis and also examined the SED effects on remodeling breast tumor microenvironment during SED-induced breast tumorigenesis. We found SED (diet with 125 g/kg sucrose), at a concentration equivalent to the average sugar consumption of American population, significantly increased the 4T1 orthotopic tumor weights by 3.7-fold in average compared to the isocaloric cornstarch control diet group. We obtained data showing tha...

Research paper thumbnail of The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Is Synergistic With Radiotherapy in Models of Human Glioblastoma

Frontiers in Pharmacology, 2022

Glioblastoma multiforme (GBM) is the most common as well as one of the most malignant types of br... more Glioblastoma multiforme (GBM) is the most common as well as one of the most malignant types of brain cancer. Despite progress in development of novel therapies for the treatment of GBM, it remains largely incurable with a poor prognosis and a very low life expectancy. Recent studies have shown that oleandrin, a unique cardiac glycoside from Nerium oleander, as well as a defined extract (PBI-05204) that contains this molecule, inhibit growth of human glioblastoma, and modulate glioblastoma patient-derived stem cell-renewal properties. Here we demonstrate that PBI-05204 treatment leads to an increase in vitro in the sensitivity of GBM cells to radiation in which the main mechanisms are the transition from autophagy to apoptosis, enhanced DNA damage and reduced DNA repair after radiotherapy (RT) administration. The combination of PBI-05204 with RT was associated with reduced tumor progression evidenced by both subcutaneous as well as orthotopic implanted GBM tumors. Collectively, these...

Research paper thumbnail of Interview by author

MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice

Research paper thumbnail of Heat-Induced SIRT1-Mediated H4K16ac Deacetylation Impairs Resection and SMARCAD1 Recruitment to Double Strand Breaks

SSRN Electronic Journal, 2022

Research paper thumbnail of α Actinin 4 potentiates MEF2 transcription activity by antagonizing HDAC7

Research paper thumbnail of Constitutive and ligand-induced EGFR signaling triggers distinct and

mutually exclusive downstream signaling networks

Research paper thumbnail of HP1β Chromo Shadow Domain facilitates H2A ubiquitination for BRCA1 recruitment at DNA double-strand breaks

Efficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated ... more Efficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we report that Heterochromatin Protein1 beta (HP1β) acts as a key component of the HR DNA resection step by regulating BRCA1 enrichment at DNA damage sites, a function largely dependent on the HP1β chromo shadow domain (CSD). HP1β itself is enriched at DSBs within gene-rich regions through a CSD interaction with Chromatin Assembly Factor 1 (CAF1) and HP1 β depletion impairs subsequent BRCA1 enrichment. An added interaction of the HP1 β CSD with the Polycomb Repressor Complex 1 ubiquitinase component RING1A facilitates BRCA1 recruitment by increasing H2A lysine 118-119 ubiquitination, a marker for BRCA1 recruitment. Our findings reveal that HP1β interactions, mediated through its CSD with RING1A, promote H2A ubiquitination and facilitate BRCA1 recruitment at DNA dam...

Research paper thumbnail of Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells

British journal of cancer, 2011

Brain tumours present unique challenges to conventional therapies and pose major health problems ... more Brain tumours present unique challenges to conventional therapies and pose major health problems around the world. Brain tumour stem cells (BTSCs) represent a small fraction of tumour cells that maintain growth, drug resistance and recurrence properties. Constitutive androstane receptor (CAR) is a nuclear receptor transcription factor that regulates drug metabolism and homoeostasis. In this study, we examined the effect of CAR agonist, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl)oxime (CITCO) on BTSCs. The expression of CAR in BTSCs was detected by quantitative RT-PCR and western blot. The antiproliferative effect of CITCO on BTSCs was determined by WST-1 and (3)H thymidine uptake assays. The effect of CITCO on CD133 expression, cell cycle progression and apoptosis in BTSCs was analysed by immunostaining and flow cytometry. The in vivo effect of CITCO was studied using subcutaneous (s.c.) BTSC xenograft in nude mice. We show for the first time t...

Research paper thumbnail of PPAR Regulation of Inflammatory Signaling in CNS Diseases

PPAR Research, 2008

Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates w... more Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates with many CNS diseases. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate immune and inflammatory responses. Specific ligands for PPAR, , and isoforms have proven effective in the animal models of multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, and trauma/stroke, suggesting their use in the treatment of neuroinflammatory diseases. The activation of NF-B and Jak-Stat signaling pathways and secretion of inflammatory cytokines are critical in the pathogenesis of CNS diseases. Interestingly, PPAR agonists mitigate CNS disease by modulating inflammatory signaling network in immune cells. In this manuscript, we review the current knowledge on how PPARs regulate neuroinflammatory signaling networks in CNS diseases.

Research paper thumbnail of Targeting PPAR as a therapy to treat multiple sclerosis

Expert Opinion on Therapeutic Targets, 2008

Multiple sclerosis (MS) is a neurological disorder that causes chronic paralysis and immense soci... more Multiple sclerosis (MS) is a neurological disorder that causes chronic paralysis and immense socio-economic problem among young adults. The etiology of MS is not known but it is generally viewed as an autoimmune inflammatory disease of the CNS. Over the past decade, several anti-inflammatory drugs have been developed to control MS symptoms but there is no medical cure. To evaluate the use and mechanism of action of agonists of PPAR, a family of nuclear receptor transcription factors that regulate inflammation, in treatment of MS. There are several reports showing beneficial effects of PPAR agonists in treating MS-like disease in animal models. We review recent advances in this field. PPAR agonists regulate MS-like disease in animal models by blocking inflammatory signaling pathways, suggesting their use in treatment of MS. Current human trials are likely to confirm the safety and efficacy of PPAR agonists for MS treatment.

Research paper thumbnail of PPARδ deficient mice develop elevated Th1/Th17 responses and prolonged experimental autoimmune encephalomyelitis

Brain Research, 2011

Multiple sclerosis (MS) is a neurological disorder that affects more than a million people worldw... more Multiple sclerosis (MS) is a neurological disorder that affects more than a million people worldwide. The etiology of MS is not known and there is no medical treatment that can cure MS. Earlier studies have shown that peroxisome proliferator-activated receptor (PPARs) agonists ameliorate MS-like disease in experimental allergic encephalomyelitis (EAE). In this study we have used PPARδ deficient mice to determine its physiological role in the regulation of CNS EAE and MS. We found that PPARδ −/− mice develop EAE with similar day of onset and disease incidence compared to C57BL/6 wild type mice. Interestingly, both male and female PPARδ −/− mice showed prolonged EAE with resistance to remission and recovery. PPARδ −/− mice with EAE expressed elevated levels of IFNγ and IL-17 along with IL-12p35 and IL-12p40 in the brain and spleen. PPARδ −/− mice also developed augmented neural antigenspecific Th1/Th17 responses and impaired Th2/Treg responses compared to wild type mice. These findings indicate that PPARδ −/− mice develop prolonged EAE in association with augmented Th1/Th17 responses, suggesting a critical physiological role for PPARδ in the remission and recovery of EAE.

Research paper thumbnail of Familial Focal Segmental Glomerulosclerosis Associated With an ACTN4 Mutation and Paternal Germline Mosaicism

American Journal of Kidney Diseases, 2008

Mutations in the ACTN4 gene cause focal segmental glomerulosclerosis (FSGS), which shows autosoma... more Mutations in the ACTN4 gene cause focal segmental glomerulosclerosis (FSGS), which shows autosomal dominant inheritance (Online Mendelian Inheritance in Man No. 603278, FSGS1). Most patients with a diagnosis of FSGS1 show a mild to moderate degree of proteinuria during adolescence or later, and some patients gradually progress to end-stage renal disease. Here, we report a familial case of FSGS1 in which 2 affected siblings showed unusual clinical, pathological, and genetic features. Both patients presented with full-blown rapidly progressing nephrotic syndrome in early childhood. Renal pathological findings were of an FSGS collapsing variant and FSGS not otherwise specified. A novel ACTN4 mutation, p.Ser262Phe, was detected in the patients, and their father was found to have a germline mosaicism for the mutation. In addition, these siblings also had a heterozygous p.Thr5Met substitution in NPHS1, which encodes nephrin, although the functional significance of this substitution is unclear. This is the third clinical report of FSGS1 and the first case report of germline mosaicism confirmed in patients with hereditary podocyte disorders. FSGS1 may have widely variable clinical and pathological phenotypes and therefore should be considered in young children with full-blown and rapidly progressing nephrotic syndrome. The possibility of germline mosaicism makes interpretation of molecular diagnoses and genetic counseling more difficult.

Research paper thumbnail of The Actin-binding Protein, Actinin Alpha 4 (ACTN4), Is a Nuclear Receptor Coactivator that Promotes Proliferation of MCF-7 Breast Cancer Cells

Journal of Biological Chemistry, 2011

Alpha actinins (ACTNs) are known for their ability to modulate cytoskeletal organization and cell... more Alpha actinins (ACTNs) are known for their ability to modulate cytoskeletal organization and cell motility by cross-linking actin filaments. We show here that ACTN4 harbors a functional LXXLL receptor interaction motif, interacts with nuclear receptors in vitro and in mammalian cells, and potently activates transcription mediated by nuclear receptors. Whereas overexpression of ACTN4 potentiates estrogen receptor ␣ (ER␣)-mediated transcription in transient transfection reporter assays, knockdown of ACTN4 decreases it. In contrast, histone deacetylase 7 (HDAC7) inhibits estrogen receptor ␣ (ER␣)-mediated transcription. Moreover, the ACTN4 mutant lacking the CaM (calmodulin)-like domain that is required for its interaction with HDAC7 fails to activate transcription by ER␣. Chromatin immunoprecipitation (ChIP) assays demonstrate that maximal associations of ACTN4 and HDAC7 with the pS2 promoter are mutually exclusive. Knockdown of ACTN4 significantly decreases the expression of ER␣ target genes including pS2 and PR and also affects cell proliferation of MCF-7 breast cancer cells with or without hormone, whereas knockdown of HDAC7 exhibits opposite effects. Interestingly, overexpression of wild-type ACTN4, but not the mutants defective in interacting with ER␣ or HDAC7, results in an increase in pS2 and PR mRNA accumulation in a hormone-dependent manner. In summary, we have identified ACTN4 as a novel, atypical coactivator that regulates transcription networks to control cell growth.

Research paper thumbnail of {alpha} Actinin 4 potentiates MEF2 transcription activity by antagonizing HDAC7

Research paper thumbnail of MCF-7 Breast Cancer Cells Coactivator that Promotes Proliferation of (ACTN4), Is a Nuclear Receptor The Actin-binding Protein, Actinin Alpha 4

Research paper thumbnail of An EGFR wild type–EGFRvIII–HB-EGF feed-forward loop regulates the activation of EGFRvIII

Research paper thumbnail of Targeting Glutamine Metabolism with a Novel Na+/K+-ATPase Inhibitor RX108 in Hepatocellular Carcinoma

Molecular Cancer Therapeutics, Feb 10, 2023

The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the ... more The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the most common form of liver cancer, highlight the urgent need to identify novel therapeutic modalities. Here, we describe the antitumor activity and underlying molecular mechanisms of a novel Na+/K+-ATPase inhibitor RX108 in human HCC cells and its xenograft model. RX108 dose-dependently inhibited HCC cell proliferation in vitro and tumor growth in a xenograft mouse model, and that the inhibition was associated with induction of apoptosis. Mechanistically, RX108 significantly downregulated alanine serine cysteine transporter 2 (ASCT2) protein expression and reduced glutamine and glutamate concentration in HCC cells and tumors. In addition, RX108 exposure led to a significant decrease in cell energy metabolism in Huh7 and Hep3B cells, including decreased levels of glutathione, NADH, NADPH, and mitochondrial respiration oxygen consumption rate. Furthermore, HCC cells exhibited evidence of glutamine addiction; the antiproliferative effect of RX108 was dependent on glutamine transport. Clinically, elevated ASCT2 mRNA expression in HCCs was associated with unfavorable survival. Taken together, these findings reveal a novel approach to target glutamine metabolism through inhibiting Na+/K+-ATPase and provide a rationale for using RX108 to treat HCC in patients whose tumors express ASCT2 at high levels. RX108 is currently under clinical development.

Research paper thumbnail of Figure S1-S5 from Targeting Glutamine Metabolism with a Novel Na+/K+-ATPase Inhibitor RX108 in Hepatocellular Carcinoma

Supplemental Figures S1-S5

Research paper thumbnail of Abstract 5075: PBI-05204, a supercritical CO2 extract of Nerium oleander, suppresses the stemness of glioblastoma stem cells and inhibits the Shh-Gli1-NANOG axis

Cancer Research

Glioblastoma multiforme (GBM) is an aggressive form of primary brain neoplasm that has a poor pro... more Glioblastoma multiforme (GBM) is an aggressive form of primary brain neoplasm that has a poor prognosis and is resistant to conventional treatment. There is a great need to develop new strategies to improve the outcome of this disease. PBI-05204, a supercritical CO2 Nerium oleander extract containing cardiac glycosides, such as oleandrin, has been tested in Phase I and II clinical trials for treatment of solid tumors. The purpose of the present study was to examine the efficacy of PBI-05204 against GBM and to explore potential mechanisms of action. Rapid growth of GBM has been associated with the presence of pluripotent cancer stem cells that have the capacity of self-renewal, proliferation, and formation of cancer progenitor cells. Genome wide expression profiling of Glioblastoma stem cells (GSCs) demonstrates similarities to embryonic stem cells (ESCs) and progenitor cells defining a pattern of hierarchical appearance of Embryonic stem cell markers: NANOG, SOX2, and GFAP. Using cu...

Research paper thumbnail of Abstract 5382: Biofield therapy suppressed the growth of human pancreatic cancer cells by modulation of cell cycle and cell voltage potentials

Cancer Research

Biofield therapies have gained popularity and are being explored as possible treatments for cance... more Biofield therapies have gained popularity and are being explored as possible treatments for cancer. In some cases, devices have been developed that mimic the electromagnetic fields (EMF) that are emitted from people delivering biofield therapies. However, it is not clear if EMFs are the mechanism of action. We previously reported that biofield therapy significantly inhibited the growth of lung cancer cells in vitro and their relevant animal model mediated through inflammatory and immune pathways. We expanded this research to examine the effects of human biofield therapy on the growth of pancreatic ductal adenocarcinoma (PDAC) cells and explored relevant mechanisms. Cell viability of human pancreatic cancer Panc-1 and mouse pancreatic cancer Panc02 cells was measured by PrestoBlue assay. Cell cycle was measured by PI staining and cell voltage potentials were assessed using DiBAC4 staining. It is well-established that cancer cells have distinct bioelectrical properties and most have d...

Research paper thumbnail of Abstract 5954: Dietary sugar promotes breast tumorigenesis partially through upregulating 12 lipoxygenase/PPARd signaling and remodeling breast tumor microenvironment

Cancer Research

Ample evidence from epidemiological studies links high-sugar diets with increased breast cancer r... more Ample evidence from epidemiological studies links high-sugar diets with increased breast cancer risk, but the underlying molecular mechanisms remain unclear. We previously reported that sucrose-enriched diets (SED) accelerated breast tumorigenesis in MMTV-ErbB2 mice and promoted the breast tumor growth in orthotopic models of mouse (4T1) or human breast cancer cells (MDA-MB-231) by up-regulating 12-lipoxygenase (12-LOX) and its arachidonate metabolite 12-HETE. In this report, we performed mechanistic studies to determine the role of 12-LOX in SED-induced breast tumorigenesis and also examined the SED effects on remodeling breast tumor microenvironment during SED-induced breast tumorigenesis. We found SED (diet with 125 g/kg sucrose), at a concentration equivalent to the average sugar consumption of American population, significantly increased the 4T1 orthotopic tumor weights by 3.7-fold in average compared to the isocaloric cornstarch control diet group. We obtained data showing tha...

Research paper thumbnail of The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Is Synergistic With Radiotherapy in Models of Human Glioblastoma

Frontiers in Pharmacology, 2022

Glioblastoma multiforme (GBM) is the most common as well as one of the most malignant types of br... more Glioblastoma multiforme (GBM) is the most common as well as one of the most malignant types of brain cancer. Despite progress in development of novel therapies for the treatment of GBM, it remains largely incurable with a poor prognosis and a very low life expectancy. Recent studies have shown that oleandrin, a unique cardiac glycoside from Nerium oleander, as well as a defined extract (PBI-05204) that contains this molecule, inhibit growth of human glioblastoma, and modulate glioblastoma patient-derived stem cell-renewal properties. Here we demonstrate that PBI-05204 treatment leads to an increase in vitro in the sensitivity of GBM cells to radiation in which the main mechanisms are the transition from autophagy to apoptosis, enhanced DNA damage and reduced DNA repair after radiotherapy (RT) administration. The combination of PBI-05204 with RT was associated with reduced tumor progression evidenced by both subcutaneous as well as orthotopic implanted GBM tumors. Collectively, these...

Research paper thumbnail of Interview by author

MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice

Research paper thumbnail of Heat-Induced SIRT1-Mediated H4K16ac Deacetylation Impairs Resection and SMARCAD1 Recruitment to Double Strand Breaks

SSRN Electronic Journal, 2022

Research paper thumbnail of α Actinin 4 potentiates MEF2 transcription activity by antagonizing HDAC7

Research paper thumbnail of Constitutive and ligand-induced EGFR signaling triggers distinct and

mutually exclusive downstream signaling networks

Research paper thumbnail of HP1β Chromo Shadow Domain facilitates H2A ubiquitination for BRCA1 recruitment at DNA double-strand breaks

Efficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated ... more Efficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we report that Heterochromatin Protein1 beta (HP1β) acts as a key component of the HR DNA resection step by regulating BRCA1 enrichment at DNA damage sites, a function largely dependent on the HP1β chromo shadow domain (CSD). HP1β itself is enriched at DSBs within gene-rich regions through a CSD interaction with Chromatin Assembly Factor 1 (CAF1) and HP1 β depletion impairs subsequent BRCA1 enrichment. An added interaction of the HP1 β CSD with the Polycomb Repressor Complex 1 ubiquitinase component RING1A facilitates BRCA1 recruitment by increasing H2A lysine 118-119 ubiquitination, a marker for BRCA1 recruitment. Our findings reveal that HP1β interactions, mediated through its CSD with RING1A, promote H2A ubiquitination and facilitate BRCA1 recruitment at DNA dam...

Research paper thumbnail of Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells

British journal of cancer, 2011

Brain tumours present unique challenges to conventional therapies and pose major health problems ... more Brain tumours present unique challenges to conventional therapies and pose major health problems around the world. Brain tumour stem cells (BTSCs) represent a small fraction of tumour cells that maintain growth, drug resistance and recurrence properties. Constitutive androstane receptor (CAR) is a nuclear receptor transcription factor that regulates drug metabolism and homoeostasis. In this study, we examined the effect of CAR agonist, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl)oxime (CITCO) on BTSCs. The expression of CAR in BTSCs was detected by quantitative RT-PCR and western blot. The antiproliferative effect of CITCO on BTSCs was determined by WST-1 and (3)H thymidine uptake assays. The effect of CITCO on CD133 expression, cell cycle progression and apoptosis in BTSCs was analysed by immunostaining and flow cytometry. The in vivo effect of CITCO was studied using subcutaneous (s.c.) BTSC xenograft in nude mice. We show for the first time t...

Research paper thumbnail of PPAR Regulation of Inflammatory Signaling in CNS Diseases

PPAR Research, 2008

Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates w... more Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates with many CNS diseases. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate immune and inflammatory responses. Specific ligands for PPAR, , and isoforms have proven effective in the animal models of multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, and trauma/stroke, suggesting their use in the treatment of neuroinflammatory diseases. The activation of NF-B and Jak-Stat signaling pathways and secretion of inflammatory cytokines are critical in the pathogenesis of CNS diseases. Interestingly, PPAR agonists mitigate CNS disease by modulating inflammatory signaling network in immune cells. In this manuscript, we review the current knowledge on how PPARs regulate neuroinflammatory signaling networks in CNS diseases.

Research paper thumbnail of Targeting PPAR as a therapy to treat multiple sclerosis

Expert Opinion on Therapeutic Targets, 2008

Multiple sclerosis (MS) is a neurological disorder that causes chronic paralysis and immense soci... more Multiple sclerosis (MS) is a neurological disorder that causes chronic paralysis and immense socio-economic problem among young adults. The etiology of MS is not known but it is generally viewed as an autoimmune inflammatory disease of the CNS. Over the past decade, several anti-inflammatory drugs have been developed to control MS symptoms but there is no medical cure. To evaluate the use and mechanism of action of agonists of PPAR, a family of nuclear receptor transcription factors that regulate inflammation, in treatment of MS. There are several reports showing beneficial effects of PPAR agonists in treating MS-like disease in animal models. We review recent advances in this field. PPAR agonists regulate MS-like disease in animal models by blocking inflammatory signaling pathways, suggesting their use in treatment of MS. Current human trials are likely to confirm the safety and efficacy of PPAR agonists for MS treatment.

Research paper thumbnail of PPARδ deficient mice develop elevated Th1/Th17 responses and prolonged experimental autoimmune encephalomyelitis

Brain Research, 2011

Multiple sclerosis (MS) is a neurological disorder that affects more than a million people worldw... more Multiple sclerosis (MS) is a neurological disorder that affects more than a million people worldwide. The etiology of MS is not known and there is no medical treatment that can cure MS. Earlier studies have shown that peroxisome proliferator-activated receptor (PPARs) agonists ameliorate MS-like disease in experimental allergic encephalomyelitis (EAE). In this study we have used PPARδ deficient mice to determine its physiological role in the regulation of CNS EAE and MS. We found that PPARδ −/− mice develop EAE with similar day of onset and disease incidence compared to C57BL/6 wild type mice. Interestingly, both male and female PPARδ −/− mice showed prolonged EAE with resistance to remission and recovery. PPARδ −/− mice with EAE expressed elevated levels of IFNγ and IL-17 along with IL-12p35 and IL-12p40 in the brain and spleen. PPARδ −/− mice also developed augmented neural antigenspecific Th1/Th17 responses and impaired Th2/Treg responses compared to wild type mice. These findings indicate that PPARδ −/− mice develop prolonged EAE in association with augmented Th1/Th17 responses, suggesting a critical physiological role for PPARδ in the remission and recovery of EAE.

Research paper thumbnail of Familial Focal Segmental Glomerulosclerosis Associated With an ACTN4 Mutation and Paternal Germline Mosaicism

American Journal of Kidney Diseases, 2008

Mutations in the ACTN4 gene cause focal segmental glomerulosclerosis (FSGS), which shows autosoma... more Mutations in the ACTN4 gene cause focal segmental glomerulosclerosis (FSGS), which shows autosomal dominant inheritance (Online Mendelian Inheritance in Man No. 603278, FSGS1). Most patients with a diagnosis of FSGS1 show a mild to moderate degree of proteinuria during adolescence or later, and some patients gradually progress to end-stage renal disease. Here, we report a familial case of FSGS1 in which 2 affected siblings showed unusual clinical, pathological, and genetic features. Both patients presented with full-blown rapidly progressing nephrotic syndrome in early childhood. Renal pathological findings were of an FSGS collapsing variant and FSGS not otherwise specified. A novel ACTN4 mutation, p.Ser262Phe, was detected in the patients, and their father was found to have a germline mosaicism for the mutation. In addition, these siblings also had a heterozygous p.Thr5Met substitution in NPHS1, which encodes nephrin, although the functional significance of this substitution is unclear. This is the third clinical report of FSGS1 and the first case report of germline mosaicism confirmed in patients with hereditary podocyte disorders. FSGS1 may have widely variable clinical and pathological phenotypes and therefore should be considered in young children with full-blown and rapidly progressing nephrotic syndrome. The possibility of germline mosaicism makes interpretation of molecular diagnoses and genetic counseling more difficult.

Research paper thumbnail of The Actin-binding Protein, Actinin Alpha 4 (ACTN4), Is a Nuclear Receptor Coactivator that Promotes Proliferation of MCF-7 Breast Cancer Cells

Journal of Biological Chemistry, 2011

Alpha actinins (ACTNs) are known for their ability to modulate cytoskeletal organization and cell... more Alpha actinins (ACTNs) are known for their ability to modulate cytoskeletal organization and cell motility by cross-linking actin filaments. We show here that ACTN4 harbors a functional LXXLL receptor interaction motif, interacts with nuclear receptors in vitro and in mammalian cells, and potently activates transcription mediated by nuclear receptors. Whereas overexpression of ACTN4 potentiates estrogen receptor ␣ (ER␣)-mediated transcription in transient transfection reporter assays, knockdown of ACTN4 decreases it. In contrast, histone deacetylase 7 (HDAC7) inhibits estrogen receptor ␣ (ER␣)-mediated transcription. Moreover, the ACTN4 mutant lacking the CaM (calmodulin)-like domain that is required for its interaction with HDAC7 fails to activate transcription by ER␣. Chromatin immunoprecipitation (ChIP) assays demonstrate that maximal associations of ACTN4 and HDAC7 with the pS2 promoter are mutually exclusive. Knockdown of ACTN4 significantly decreases the expression of ER␣ target genes including pS2 and PR and also affects cell proliferation of MCF-7 breast cancer cells with or without hormone, whereas knockdown of HDAC7 exhibits opposite effects. Interestingly, overexpression of wild-type ACTN4, but not the mutants defective in interacting with ER␣ or HDAC7, results in an increase in pS2 and PR mRNA accumulation in a hormone-dependent manner. In summary, we have identified ACTN4 as a novel, atypical coactivator that regulates transcription networks to control cell growth.

Research paper thumbnail of {alpha} Actinin 4 potentiates MEF2 transcription activity by antagonizing HDAC7

Research paper thumbnail of MCF-7 Breast Cancer Cells Coactivator that Promotes Proliferation of (ACTN4), Is a Nuclear Receptor The Actin-binding Protein, Actinin Alpha 4