Publications by authors named "Maxime Parisotto"

12 Publications

  • Page 1 of 1

Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth.

Sci Rep 2021 05 10;11(1):9854. Epub 2021 May 10.

Département de Chimie-Faculté des Arts et des Sciences, Université de Montréal, 2900 Edouard Montpetit, Succursale Centre-Ville, CP 6128, Montreal, QC, H3C3J7, Canada.

We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth of pancreatic cancer cells. We first present their in vitro and membrane activity, before we address their mechanism of action in living cells and in vivo activity. We show that phenylethynyl biguanidium salts possess higher ability to cross hydrophobic barriers, improve mitochondrial accumulation and anticancer activity. Mechanistically, the most active compound, 1b, like metformin, activated AMPK, decreased the NAD/NADH ratio and mitochondrial respiration, but at 800-fold lower concentration. In vivo studies show that compound 1b significantly inhibits the growth of pancreatic cancer xenografts in mice, while biguanides currently in clinical trials had little activity.
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http://dx.doi.org/10.1038/s41598-021-87993-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110578PMC
May 2021

Myod1 and GR coordinate myofiber-specific transcriptional enhancers.

Nucleic Acids Res 2021 05;49(8):4472-4492

Université de Strasbourg, CNRS UMR7104, INSERM U1258, IGBMC, F-67400 Illkirch, France.

Skeletal muscle is a dynamic tissue the size of which can be remodeled through the concerted actions of various cues. Here, we investigated the skeletal muscle transcriptional program and identified key tissue-specific regulatory genetic elements. Our results show that Myod1 is bound to numerous skeletal muscle enhancers in collaboration with the glucocorticoid receptor (GR) to control gene expression. Remarkably, transcriptional activation controlled by these factors occurs through direct contacts with the promoter region of target genes, via the CpG-bound transcription factor Nrf1, and the formation of Ctcf-anchored chromatin loops, in a myofiber-specific manner. Moreover, we demonstrate that GR negatively controls muscle mass and strength in mice by down-regulating anabolic pathways. Taken together, our data establish Myod1, GR and Nrf1 as key players of muscle-specific enhancer-promoter communication that orchestrate myofiber size regulation.
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http://dx.doi.org/10.1093/nar/gkab226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096230PMC
May 2021

Senescence controls prostatic neoplasia driven by Pten loss.

Mol Cell Oncol 2019 23;6(1):1511205. Epub 2018 Nov 23.

Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.

We report that Pten (phosphatase and tensin homologue) ablation in prostatic epithelial cells of adult mice promotes cell proliferation to generate prostatic intraepithelial neoplasia. Moreover, our results demonstrate that proliferating Pten-deficient cells undergo replication stress and exhibit a DNA damage response, leading to cell senescence, as seen in oncogene-induced senescence.
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http://dx.doi.org/10.1080/23723556.2018.1511205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370383PMC
November 2018

Circumventing senescence is associated with stem cell properties and metformin sensitivity.

Aging Cell 2019 04 6;18(2):e12889. Epub 2019 Jan 6.

Department of Biochemistry and Molecular Medicine and CR-CHUM, Université de Montréal, Montréal, Québec, Canada.

Most cancers arise in old individuals, which also accumulate senescent cells. Cellular senescence can be experimentally induced by expression of oncogenes or telomere shortening during serial passage in culture. In vivo, precursor lesions of several cancer types accumulate senescent cells, which are thought to represent a barrier to malignant progression and a response to the aberrant activation of growth signaling pathways by oncogenes (oncogene toxicity). Here, we sought to define gene expression changes associated with cells that bypass senescence induced by oncogenic RAS. In the context of pancreatic ductal adenocarcinoma (PDAC), oncogenic KRAS induces benign pancreatic intraepithelial neoplasias (PanINs), which exhibit features of oncogene-induced senescence. We found that the bypass of senescence in PanINs leads to malignant PDAC cells characterized by gene signatures of epithelial-mesenchymal transition, stem cells, and mitochondria. Stem cell properties were similarly acquired in PanIN cells treated with LPS, and in primary fibroblasts and mammary epithelial cells that bypassed Ras-induced senescence after reduction of ERK signaling. Intriguingly, maintenance of cells that circumvented senescence and acquired stem cell properties was blocked by metformin, an inhibitor of complex I of the electron transport chain or depletion of STAT3, a protein required for mitochondrial functions and stemness. Thus, our studies link bypass of senescence in premalignant lesions to loss of differentiation, acquisition of stemness features, and increased reliance on mitochondrial functions.
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http://dx.doi.org/10.1111/acel.12889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413657PMC
April 2019

[How to limit the progression of PTEN-deficient prostatic tumors?]

Med Sci (Paris) 2018 Nov 10;34(11):904-906. Epub 2018 Dec 10.

Institut de génétique et de biologie moléculaire et cellulaire (IGBMC), CNRS UMR7104, Inserm U1251, université de Strasbourg, 1 rue Laurent Fries, 67400 Illkirch, France.

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http://dx.doi.org/10.1051/medsci/2018224DOI Listing
November 2018

Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides.

Cell Metab 2018 12 20;28(6):817-832.e8. Epub 2018 Sep 20.

Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada. Electronic address:

There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine, and serine synthesis by modulating mRNA translation, while ablation of 4E-BP1/2 substantially decreases sensitivity of breast cancer and melanoma cells to KI/biguanide combinations. Efficacy of the KI/biguanide combinations is also determined by HIF-1α-dependent perturbations in glutamine metabolism, which were observed in VHL-deficient renal cancer cells. This suggests that cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms, which allows them to survive therapeutic insults that target cancer metabolism.
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http://dx.doi.org/10.1016/j.cmet.2018.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252493PMC
December 2018

deletion in luminal cells of mature prostate induces replication stress and senescence in vivo.

J Exp Med 2018 06 9;215(6):1749-1763. Epub 2018 May 9.

Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U1258, Université de Strasbourg, Illkirch Cedex, France

Genetic ablation of the tumor suppressor in prostatic epithelial cells (PECs) induces cell senescence. However, unlike oncogene-induced senescence, no hyperproliferation phase and no signs of DNA damage response (DDR) were observed in -deficient PECs; loss-induced senescence (PICS) was reported to be a novel type of cellular senescence. Our study reveals that ablation in prostatic luminal epithelial cells of adult mice stimulates PEC proliferation, followed by a progressive growth arrest with characteristics of cell senescence. Importantly, we also show that proliferating -deficient PECs undergo replication stress and mount a DDR leading to p53 stabilization, which is however delayed by Mdm2-mediated p53 down-regulation. Thus, even though -deficiency induces cellular senescence that restrains tumor progression, as it involves replication stress, strategies promoting loss-induced senescence are at risk for cancer prevention and therapy.
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http://dx.doi.org/10.1084/jem.20171207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987915PMC
June 2018

Genetically engineered mouse models of prostate cancer.

Mol Oncol 2013 Apr 14;7(2):190-205. Epub 2013 Feb 14.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, Inserm U964, Université de Strasbourg, Collège de France, Department of Functional Genomics and Cancer, 67404 Illkirch, France.

Despite major improvement in treatment of early stage localised prostate cancer, the distinction between indolent tumors and those that will become aggressive, as well as the lack of efficient therapies of advanced prostate cancer, remain major health problems. Genetically engineered mice (GEM) have been extensively used to investigate the molecular and cellular mechanisms underlying prostate tumor initiation and progression, and to evaluate new therapies. Moreover, the recent development of conditional somatic mutagenesis in the mouse prostate offers the possibility to generate new models that more faithfully reproduce the human disease, and thus should contribute to improve diagnosis and treatments. The strengths and weaknesses of various models will be discussed, as well as future opportunities.
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http://dx.doi.org/10.1016/j.molonc.2013.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528413PMC
April 2013

Kinetic characterization of recombinant mouse retinal dehydrogenase types 3 and 4 for retinal substrates.

Biochim Biophys Acta 2009 Dec 18;1790(12):1660-4. Epub 2009 Sep 18.

Laboratory of Nutrition and Cancer, Centre de recherché du Centre hospitalier de l'Université de Montréal (CRCHUM), Hôtel-Dieu, and the Department of Medicine Université de Montréal, Montreal, Quebec, Canada.

Background: Retinal dehydrogenases (RALDHs) catalyze the dehydrogenation of retinal into retinoic acids (RAs), which are required for embryogenesis and tissue differentiation. This study sought to determine the detailed kinetic properties of 2 mouse RALDHs, namely RALDH3 and 4, for retinal isomer substrates, to better define their specificities in RA isomer synthesis.

Methods: RALDH3 and 4 were expressed in Escherichia coli as His-tagged proteins and affinity-purified. Enzyme kinetics were performed with retinal isomer substrates. The enzymatic products were analyzed by high pressure liquid chromatography.

Results: RALDH3 oxidized all-trans retinal with high catalytic efficiency (Vmax/Km=77.9) but did not show activity for either 9-cis or 13-cis retinal substrates. On the other hand, RALDH4 was inactive for all-trans retinal substrate, exhibited high activity for 9-cis retinal oxidation (Vmax/Km=27.4), and oxidized 13-cis retinal with lower catalytic efficiency (Vmax/Km=8.24). beta-ionone, a potent inhibitor of RALDH4 activity, suppressed 9-cis and 13-cis retinal oxidation competitively with inhibition constants of 0.60 and 0.32, respectively, but had no effect on RALDH3 activity. The divalent cation MgCl2 activated 13-cis retinal oxidation by RALDH4 by 3-fold, did not significantly influence 9-cis retinal oxidation, and slightly activated RALDH3 activity.

Conclusions: These data extend the kinetic characterization of RALDH3 and 4, providing their specificities for retinal isomer substrates.

General Significance: The kinetic characterization of RALDHs should give useful information in determining amino acid residues that are involved in the specificity for retinal isomers and on the role of these enzymes in the synthesis of RAs in specific tissues.
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http://dx.doi.org/10.1016/j.bbagen.2009.09.004DOI Listing
December 2009

Isomer-specific retinoic acid biosynthesis in HeLa cells expressing recombinant class I aldehyde dehydrogenases.

Biochim Biophys Acta 2007 Nov 17;1770(11):1548-56. Epub 2007 Aug 17.

Laboratory of Nutrition and Cancer, Centre Hospitalier de l'Université de Montréal-Hotel Dieu, Canada.

Retinal dehydrogenase type 1 (RALDH1) catalyzes the oxidation of all-trans and 9-cis retinal to the respective retinoic acids (RAs), whereas another member of the aldehyde dehydrogenase family, the phenobarbital-induced aldehyde dehydrogenase (PB-ALDH), is very poorly active. We have previously generated chimeras between these two enzymes that displayed selectivity for retinal isomers in crude bacterial extracts. To examine whether the selectivity of the recombinant enzymes is retained in intact cells, we first assessed whether retinoid-isomerizing activity is present in cultured eukaryotic cells. Our results demonstrate that the only RA isomers detected in RALDH1-expressing or non-expressing cells corresponded to the same steric conformation as the supplied retinoids, indicating a lack of measurable 9-cis/all-trans retinoid-isomerizing activity. Finally, HeLa cells transfected with RALDH1 derivatives that were retinal isomer-selective in vitro produced only the corresponding RA isomers, establishing these enzymes as useful tools to assess the respective roles of the two RA isomers in vivo.
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http://dx.doi.org/10.1016/j.bbagen.2007.07.013DOI Listing
November 2007

Kinetic properties of chimeric class I aldehyde dehydrogenases for retinal isomers.

Biochem Cell Biol 2006 Oct;84(5):799-804

Laboratory of Nutrition and Cancer, Centre Hospitalier de l'Université de Montréal-Hotel Dieu, Université de Montréal, 3850 Saint Urbain St, Montréal, QC H2W 1T7, Canada.

Retinal dehydrogenase type 1 (RALDH1) catalyzes the oxidation of all-trans and 9-cis retinal to the respective retinoic acids (RAs), whereas another member of the aldehyde dehydrogenase (ALDH) family, the phenobarbital-induced aldehyde dehydrogenase (PB-ALDH), is very poorly active. We have previously generated chimeras between these 2 enzymes that displayed selectivity for retinal isomers in crude bacterial extracts. Here we have characterized the kinetic properties of the corresponding purified recombinant proteins. The all-trans selective chimera RALDH-131 converted all-trans retinal to all-trans RA with 2.9-fold lower efficiency than the wild-type RALDH1 and had only residual activity with 9-cis retinal. The converse chimera PB-131 was specific for 9-cis retinal, with no residual activity for all-trans retinal. MgCl2 inhibited the activities of RALDH1 and PB-131, but not of RALDH-131, suggesting that amino acids 132-510 in RALDH are necessary for inhibition by MgCl2. These data demonstrate that the chimeric enzymes act as retinal isomer-selective ALDHs, and suggest that these enzymes may be useful to study the roles of cis RA isomers in embryogenesis and differentiation in vivo.
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http://dx.doi.org/10.1139/o06-038DOI Listing
October 2006

[Retinoid metabolism and cancer].

Med Sci (Paris) 2006 Dec;22(12):1101-6

Département de biochimie et Institut de recherche en immunologie et cancérologie, Université de Montréal, CP 6128, succursale Centre-ville, Montréal (Québec), H3C 3J7 Canada.

Retinoids play important roles in cell differentiation and apoptosis, notably in epithelial tissues. Their utility in cancer therapy has been demonstrated in specific cancer types. Use of retinoic acid (RA) in the treatment of acute promyelocytic leukemia was the first successful example of retinoid-based differentiation therapy. RA has since been evaluated for treatment of other cancers, revealing variable effectiveness. The observation that expression of enzymes involved in RA biosynthesis is suppressed during tumorigenesis suggests that intra-tumor depletion in RA levels may contribute to tumor development and argues for the use of retinoids in cancer treatment. However, the induction of RA-inactivating enzymes is one of the mechanisms that may limit the efficacy of retinoid therapy and contribute to acquired resistance to RA treatment, suggesting that retinoic acid metabolism blocking agents may be effective agents in differentiation therapy.
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http://dx.doi.org/10.1051/medsci/200622121101DOI Listing
December 2006
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