Mineko Terao | Mario Negri Institute for Pharmacological Research. Milan, IT (original) (raw)

Papers by Mineko Terao

Current Opinion in Pharmacology, Aug 1, 2001

Cytodifferentiation therapy promises to control cancer growth and progression with less serious s... more Cytodifferentiation therapy promises to control cancer growth and progression with less serious side effects than cytotoxic chemotherapy. Despite recent progress, the molecular mechanisms regulating the differentiation of many cell types are still obscure and the number of active cytodifferentiating agents is limited. Rational ways to develop these types of agents are necessary.

Xanthine Oxidoreductase and Aldehyde Oxidases

Elsevier eBooks, 2018

Aldehyde oxidases (AOXs) and xanthine oxidoreductase (XOR) are closely related enzymes with very ... more Aldehyde oxidases (AOXs) and xanthine oxidoreductase (XOR) are closely related enzymes with very similar primary structures comprising two identical subunits each of which contains four redox centers: one molybdopterin cofactor, one flavin adenine dinucleotide (oxidized form) molecule, and two iron–sulfur clusters. The enzymes, also referred to as molybdenum hydroxylases, catalyze both oxidation and reduction reactions and play a significant role in the metabolism of drugs and endobiotics including endogenous purines. Generally, oxidation reactions involve nucleophilic attack via a Mo–OH ligand at a carbon atom in N -heterocycles and aldehydes with electrons transferred ultimately to molecular oxygen or NAD + (nicotinamide adenine dinucleotide—the oxidized form). Reduction of oxygen can generate reactive oxygen species, which have been implicated in a variety of protective and pathophysiological functions. AOXs and XOR are widely distributed throughout the animal kingdom and probably originated from a single ancestor gene coding for a dehydrogenase form of XOR. While a single mammalian XOR is known, various mammalian AOX isoenzymes have been identified. The complement of active mammalian AOX genes varies from one in humans ( AOX1 ) to four in rodents ( AOX1 , AOX2 , AOX3 , and AOX4 ). In humans, the AOX1 and XOR genes are found on different arms of chromosome 2 and are both subject to complex regulation, the precise details of which have not yet been fully characterized. The 3D structures of bovine milk XOR, human AOX1, and mouse AOX3 are available and have provided valuable information on the catalytic mechanism of molybdenum hydroxylases. This chapter provides an overview of the current knowledge on the structure, evolution, and function of these highly complex enzymes.

Journal of Chemotherapy, Nov 1, 2004

Retinoid-related molecules (RRMs) are an interesting class of novel molecules endowed with remark... more Retinoid-related molecules (RRMs) are an interesting class of novel molecules endowed with remarkable and selective apoptotic activity against various leukemia and cancer cell types. ST1926 is the most promising molecule and is active in vivo on numerous experimental models of leukemia and cancer. This has led to the development of a compound that will soon undergo phase I clinical trials. Although the primary molecular targets of RRMs' apoptotic activity are still unknown, ST1926 and congeners are characterized by a peculiar mechanism of action that centers on the mitochondrion and is associated with alterations in the homeostasis of intracellular calcium.

Data from Inhibition of the Peptidyl-Prolyl-Isomerase Pin1 Enhances the Responses of Acute Myeloid Leukemia Cells to Retinoic Acid via Stabilization of RARα and PML-RARα

The peptidyl-prolyl-isomerase Pin1 interacts with phosphorylated proteins, altering their conform... more The peptidyl-prolyl-isomerase Pin1 interacts with phosphorylated proteins, altering their conformation. The retinoic acid receptor RARα and the acute-promyelocytic-leukemia–specific counterpart PML-RARα directly interact with Pin1. Overexpression of Pin1 inhibits ligand-dependent activation of RARα and PML-RARα. Inhibition is relieved by Pin1-targeted short interfering RNAs and by pharmacologic inhibition of the catalytic activity of the protein. Mutants of Pin1 catalytically inactive or defective for client-protein–binding activity are incapable of inhibiting ligand-dependent RARα transcriptional activity. Functional inhibition of RARα and PML-RARα by Pin1 correlates with degradation of the nuclear receptors via the proteasome-dependent pathway. In the acute myelogenous leukemia cell lines HL-60 and NB4, Pin1 interacts with RARα in a constitutive fashion. Suppression of Pin1 by a specific short hairpin RNA in HL-60 or NB4 cells stabilizes RARα and PML-RARα, resulting in increased sensitivity to the cytodifferentiating and antiproliferative activities of all-trans retinoic acid. Treatment of the two cell lines and freshly isolated acute myelogenous leukemia blasts (M1 to M4) with ATRA and a pharmacologic inhibitor of Pin1 causes similar effects. Our results add a further layer of complexity to the regulation of nuclear retinoic acid receptors and suggest that Pin1 represents an important target for strategies aimed at increasing the therapeutic index of retinoids. [Cancer Res 2009;69(3):1016–26

eBioMedicine, 2020

Background: CXCL13 is a B and T lymphocyte chemokine that mediates neuroinflammation through its ... more Background: CXCL13 is a B and T lymphocyte chemokine that mediates neuroinflammation through its receptor CXCR5. This chemokine is highly expressed by motoneurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) SOD1G93A (mSOD1) mice during the disease, particularly in fast-progressing mice. Accordingly, in this study, we investigated the role of this chemokine in ALS. Methods: We used in vitro and in vivo experimental paradigms derived from ALS mice and patients to investigate the expression level and distribution of CXCL13/CXCR5 axis and its role in MN death and disease progression. Moreover, we compared the levels of CXCL13 in the CSF and serum of ALS patients and controls. Findings: CXCL13 and CXCR5 are overexpressed in the spinal MNs and peripheral axons in mSOD1 mice. CXCL13 inhibition in the CNS of ALS mice resulted in the exacerbation of motor impairment (n = 4/group; Mean_Diff.=27.81) and decrease survival (n = 14_Treated:19.2 § 1.05wks, n = 17_Controls:20.2 § 0.6wks; 95% CI: 0.4687À1.929). This was corroborated by evidence from primary spinal cultures where the inhibition or activation of CXCL13 exacerbated or prevented the MN loss. Besides, we found that CXCL13/CXCR5 axis is overexpressed in the spinal cord MNs of ALS patients, and CXCL13 levels in the CSF discriminate ALS (n = 30) from Multiple Sclerosis (n = 16) patients with a sensitivity of 97.56%. Interpretation: We hypothesise that MNs activate CXCL13 signalling to attenuate CNS inflammation and prevent the neuromuscular denervation. The low levels of CXCL13 in the CSF of ALS patients might reflect the MN dysfunction, suggesting this chemokine as a potential clinical adjunct to discriminate ALS from other neurological diseases.

Biochemical Journal, Nov 1, 1996

In the mammary gland of virgin mice, xanthine oxidoreductase (XOR) enzymic activity is barely mea... more In the mammary gland of virgin mice, xanthine oxidoreductase (XOR) enzymic activity is barely measurable. A high increase in the levels of the enzyme is observed during the last days of pregnancy and during lactation, and this is parallelled by an elevation in the amounts of the respective protein and transcript. In situ hybridization experiments demonstrate that the XOR mRNA is specifically expressed in the alveolar epithelial cells of the mammary gland. In HC11 cells, a model culture system for normal breast epithelium, the levels of XOR enzymic activity are * These two authors contributed equally to the generation of the data presented in this study.

Data from Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity

Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferativ... more Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferative activity, a different mechanism of action from classic retinoids and no cross-resistance with other chemotherapeutics. ST1926 and CD437 are prototypic RRMs, with the former currently undergoing phase I clinical trials. We show here that ST1926, CD437, and active congeners cause DNA damage. Cellular and subcellular COMET assays, H2AX phosphorylation (γ-H2AX), and scoring of chromosome aberrations indicate that active RRMs produce DNA double-strand breaks (DSB) and chromosomal lesions in NB4, an acute myeloid leukemia (AML) cell line characterized by high sensitivity to RRMs. There is a direct quantitative correlation between the levels of DSBs and the cytotoxic/antiproliferative effects induced by RRMs. NB4.437r blasts, which are selectively resistant to RRMs, do not show any sign of DNA damage after treatment with ST1926, CD437, and analogues. DNA damage is the major mechanism underlying the antileukemic activity of RRMs in NB4 and other AML cell lines. In accordance with the S-phase specificity of the cytotoxic and antiproliferative responses of AML cells to RRMs, increases in DSBs are maximal during the S phase of the cell cycle. Induction of DSBs precedes inhibition of DNA replication and is associated with rapid activation of ataxia telangectasia mutated, ataxia telangectasia RAD3-related, and DNA-dependent protein kinases with subsequent stimulation of the p38 mitogen-activated protein kinase. Inhibition of ataxia telangectasia mutated and DNA-dependent protein kinases reduces phosphorylation of H2AX. Cells defective for homologous recombination are particularly sensitive to ST1926, indicating that this process is important for the protection of cells from the RRM-dependent DNA damage and cytotoxicity. [Mol Cancer Ther 2008;7(9):2941–54]

Abstract P5-05-08: Molecular cross-talk between retinoic acid and NOTCH1 signaling pathways: Role in triple negative breast cancer

Triple Negative Breast Cancer (TNBC) represents 10-20% of all breast cancers and it is characteri... more Triple Negative Breast Cancer (TNBC) represents 10-20% of all breast cancers and it is characterized by poor prognosis and high recurrence rate. The heterogeneity of the disease and the absence of well-defined molecular targets have so far challenged successful therapeutic strategies. NOTCH1 has been found to act as a driver oncogene in a small subset of TNBC characterized by constitutive activation of the protein, acting as a transcription factor. Preclinical studies support an anti-tumor activity of All-Trans Retinoic Acid (ATRA) in specific subsets of breast cancer. By screening a large panel of breast cancer cell lines recapitulating the heterogeneity of TNBC we identify a specific subset sensitive to the anti-proliferative activity of ATRA. These cell lines (N-TNBC cell lines) are characterized by a Notch1 intragenic fusion transcript conferring gain of function activity to the protein. Indeed, sequence analysis reveals that the cell lines harbor an interstitial deletion in the NOTCH1 gene encompassing the negative regulatory region (NRR) domain. These cell lines depend on Notch active signaling for their proliferation since their cell growth is impaired by Notch inhibitors (γ-secretase inhibitors, e.g. DAPT, PF-3084014). Proliferation assays reveal that ATRA and γ-secretase inhibitors act synergistically in inhibiting cancer cell growth in N-TNBC cell lines suggesting the existence of a cross talk between the molecular pathways engaged by retinoic acid and NOTCH1. By using retinoic acid receptors (RARs) agonists and antagonists as well as RAR specific silencing experiments we identify RARα as the retinoic acid receptor responsible of the anti-proliferation activity of ATRA in N-TNBC cell lines. In particular N-TNBC cell lines respond to RARα activation by inducing high amounts of the onco-supressor protein RARβ. This feature is unique in ATRA sensitive TNBC cell lines and does not occur in ATRA sensitive luminal cell lines arguing for the existence of a retinoic acid specific mechanism of action in N-TNBC. Since RARs act as transcription factors inside the cells, to gain insights into the molecular pathway at the basis of the observed ATRA/NOTCH1 cross talk, we performed RNAseq analysis of ATRA and/or DAPT treated N-TNBC cells. Gene set enrichment analysis reveal that ATRA is able to directly affect NOTCH1 transduction pathway by modulating the expression of NOTCH1 target genes. In particular, in two out of three N-TNBC cell lines ATRA directly inhibits the NOTCH1 expression at a transcriptional level and its downregulation is increased by ATRA/DAPT combinations. Pathway analysis has allowed the identification of putative molecular hubs responsible for the synergistic effects observed and therefore likely at the basis of the crosstalk between ATRA/NOTCH pathways. These findings are of clinical interest since both the retinoid and NOTCH signaling display crucial physiologic activities and their pleiotropic effects could impinge on the success of therapeutic options based on their pathway modulation. The newly discovered specificity of ATRA action in the context of NOTCH1 addicted TNBC provides new tools for the identification of patients candidates benefitting from strategies targeting the ATRA/NOTCH axis. Citation Format: Paroni G, Zanetti A, Bolis M, Vallerga A, Troiani M, Fratelli M, Kurosaki M, Terao M, Garattini E. Molecular cross-talk between retinoic acid and NOTCH1 signaling pathways: Role in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-08.

Abstract 5543: Network guided modeling allows tumor type independent prediction of sensitivity to retinoic acid

Background: All-trans retinoic acid (ATRA) is a differentiating agent used in the treatment of ac... more Background: All-trans retinoic acid (ATRA) is a differentiating agent used in the treatment of acute-promyelocytic-leukemia and it is under-exploited in other malignancies despite its low systemic toxicity. A rational/personalized use of ATRA requires development of predictive tools allowing identification of sensitive cancer types and responsive individuals. Materials and Methods: RNA-Sequencing data for 10080 patients and 33 different tumor-types were derived from the TCGA and Leucegene datasets and completely re-processed. The study was performed using machine learning methods and network analysis. Results: We profiled a large panel of breast-cancer cell-lines for in vitro sensitivity to ATRA and exploited the associated basal gene-expression data to initially generate a model predicting ATRA-sensitivity in this disease. Starting from these results and using a network-guided approach, we developed a generalized model (ATRA-21) whose validity extends to tumor-types other than breast cancer. ATRA-21 predictions correlate with experimentally determined sensitivity in a large panel of cell-lines representative of numerous tumor-types. In patients, ATRA-21 correctly identifies APL as the most sensitive acute-myelogenous-leukemia subtype and indicates that uveal-melanoma and low-grade glioma are top-ranking diseases as for average predicted responsiveness to ATRA. There is a consistent number of tumor-types for which higher ATRA-21 predictions are associated with better outcomes. Conclusions: In summary, we generated a tumor-type independent ATRA-sensitivity predictor which consists of a restricted number of genes and has the potential to be applied in the clinics. Identification of the tumor-types which are likely to be generally sensitive to the action of ATRA paves the way to the design of clinical studies in the context of these diseases. In addition, ATRA-21 may represent an important diagnostic tool for the selection of individual patients who may benefit from ATRA-based therapeutic strategies also in tumors characterized by lower average sensitivity. Citation Format: Enrico Garattini, Marco Bolis, Maddalena Fratelli, Mineko Terao. Network guided modeling allows tumor type independent prediction of sensitivity to retinoic acid [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5543. doi:10.1158/1538-7445.AM2017-5543

Biochemical Journal, Aug 1, 1992

Human interferon-a A/D (BglII) (IFN-a A/D) and mouse interferon-y (IFN-y) are shown to induce xan... more Human interferon-a A/D (BglII) (IFN-a A/D) and mouse interferon-y (IFN-y) are shown to induce xanthine dehydrogenase (XD) mRNA in L929 fibroblastic cells. XD mRNA accumulation after IFN-a A/D treatment is relatively fast, being already evident after 4 h and reaching its maximum after 24 h. IFN-a A/D is active in inducing XD mRNA at 0.1 unit/ml and it is maximally active at 103 units/ml. The half-life of the XD message is unaffected-by IFN-c A/D treatment, whereas the transcriptional activity of the XD gene and the concentrations of XD heterogeneous nuclear RNA are increased by 2-and 6-fold respectively. The effect of IFN-a A/D on XD mRNA is insensitive to cycloheximide, suggesting that protein synthesis de novo is not required. Experiments conducted with specific inhibitors suggest that protein kinase C, cyclic AMP and arachidonic acid metabolites derived from lipoxygenase or cycloxygenase do not act as second-messenger molecules in the induction of XD mRNA by IFN-a A/D. XD mRNA is also induced in NIH3T3 fibroblastic cells, but not in F9 teratocarcinoma or B16 melanoma cells after treatment with IFN-a A/D. NIH3T3 are the only cells so far tested that have detectable XD and xanthine oxidase activities under basal conditions and after IFN-a A/D treatment, although their responsiveness to the cytokine is much less than that observed in L929 cells. MATERIALS AND METHODS Cell lines and reagents L929 is a fibroblastic cell line obtained from the American Type Culture Collection (A.T.C.C.), Rockville, MD, U.S.A. These cells were routinely passaged in RPMI 1640 containing 10 % (v/v) fetal-calf serum. F9 teratocarcinoma cells (from Dr. Abbreviations used: IFN, interferon; XD, xanthine dehydrogenase; XO, xanthine oxidase; LPS, lipopolysaccharide; poly(I/C), polyriboinosinic/ polyribocitidylic acid; 1 x SSC, 0.15 M-NaCl/0.01 5 M-sodium citrate, pH 7.0; oligoAS, oligoadenylate synthetase; ISRE, IFN-stimulated responsive element. t To whom correspondence and reprint requests should be addressed.

Mouse L929 cells are defective in the expression of xanthine oxidoreductase enzymatic activity and molybdenum (VI) salts can complement the deficit

Supplementary Fig. S3 from Atypical retinoids ST1926 and CD437 are S-phase-specific agents causin... more Supplementary Fig. S3 from Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity

Supplementary Fig. S5 from Atypical retinoids ST1926 and CD437 are S-phase-specific agents causin... more Supplementary Fig. S5 from Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity

Supplementary Fig. S2 from Atypical retinoids ST1926 and CD437 are S-phase-specific agents causin... more Supplementary Fig. S2 from Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity

BackgroundCornelia de Lange syndrome (CdLS) is a rare multisystem genetic disorder which is cause... more BackgroundCornelia de Lange syndrome (CdLS) is a rare multisystem genetic disorder which is caused by genetic defects involving the Nipped-B-like protein (NIPBL) gene in the majority of clinical cases (60-70%). Currently, there are no specific cures available for CdLS and clinical management is needed for life. Disease models are highly needed to find a cure. Among therapeutic possibilities are genome editing strategies based on CRISPR-Cas technology. MethodsWe tested CRISPR-Cas technologies including most recent base- and prime editors which introduce modifications without DNA cleavages and compared with sequence substitution approaches through homology directed (HDR) induced by Cas9 nuclease activity. The HDR method that was found more efficient was applied to repair a CdLS-causing mutation in the NIPBL gene. We generated isogenic corrected clones from human induced pluripotent stem cells (hiPSCs) obtained from a CdLS patient carrying the c.5483G>A mutation in the NIPBL gene. R...

Purification and cDNA cloning and expression of bovine liver aldehyde oxidase; similarity with xanthine dehydrogenase

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