Publications by authors named "Marie-Camille Rowell"

8 Publications

  • Page 1 of 1

A hydride transfer complex reprograms NAD metabolism and bypasses senescence.

Mol Cell 2021 Sep;81(18):3848-3865.e19

CRCHUM, 900 Saint-Denis St, Montréal, QC H2X 0A9, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada. Electronic address:

Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP. This hydride transfer complex (HTC) is assembled by malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase. HTC is found in phase-separated bodies in the cytosol of cancer or hypoxic cells and can be assembled in vitro with recombinant proteins. HTC is repressed in senescent cells but induced by p53 inactivation. HTC enzymes are highly expressed in mouse and human prostate cancer models, and their inactivation triggers senescence. Exogenous expression of HTC is sufficient to bypass senescence, rescue cells from complex I inhibitors, and cooperate with oncogenic RAS to transform primary cells. Altogether, we provide evidence for a new multi-enzymatic complex that reprograms metabolism and overcomes cellular senescence.
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http://dx.doi.org/10.1016/j.molcel.2021.08.028DOI Listing
September 2021

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

Metformin turns off the metabolic switch of pancreatic cancer.

Aging (Albany NY) 2019 12 12;11(23):10793-10795. Epub 2019 Dec 12.

CR-CHUM, Université de Montréal, Montréal, Québec, Canada.

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http://dx.doi.org/10.18632/aging.102622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932906PMC
December 2019

Phosphorylation of SOCS1 Inhibits the SOCS1-p53 Tumor Suppressor Axis.

Cancer Res 2019 07 17;79(13):3306-3319. Epub 2019 May 17.

Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, Québec, Canada.

Expression of the suppressor of cytokine signaling-1 (SOCS1) is inactivated in hematopoietic and solid cancers by promoter methylation, miRNA-mediated silencing, and mutations. Paradoxically, SOCS1 is also overexpressed in many human cancers. We report here that the ability of SOCS1 to interact with p53 and regulate cellular senescence depends on a structural motif that includes tyrosine (Y)80 in the SH2 domain of SOCS1. Mutations in this motif are found at low frequency in some human cancers, and substitution of Y80 by a phosphomimetic residue inhibits p53-SOCS1 interaction and its functional consequences, including stimulation of p53 transcriptional activity, growth arrest, and cellular senescence. Mass spectrometry confirmed SOCS1 Y80 phosphorylation in cells, and a new mAb was generated to detect its presence in tissues by IHC. A tyrosine kinase library screen identified the SRC family as Y80-SOCS1 kinases. SRC family kinase inhibitors potentiated the SOCS1-p53 pathway and reinforced SOCS1-induced senescence. Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization. Collectively, these results reveal a mechanism that inactivates the SOCS1-p53 senescence pathway and suggest that inhibition of SRC family kinases as personalized treatment in patients with lymphomas may be successful. SIGNIFICANCE: These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1503DOI Listing
July 2019

Ribosomal protein RPL22/eL22 regulates the cell cycle by acting as an inhibitor of the CDK4-cyclin D complex.

Cell Cycle 2019 Mar - Apr;18(6-7):759-770. Epub 2019 Mar 28.

a Department of Biochemistry and Molecular Medicine , Université de Montréal , Montréal , Québec , Canada.

Senescence is a tumor suppressor program characterized by a stable growth arrest while maintaining cell viability. Senescence-associated ribogenesis defects (SARD) have been shown to regulate senescence through the ability of the ribosomal protein S14 (RPS14 or uS11) to bind and inhibit the cyclin-dependent kinase 4 (CDK4). Here we report another ribosomal protein that binds and inhibits CDK4 in senescent cells: L22 (RPL22 or eL22). Enforcing the expression of RPL22/eL22 is sufficient to induce an RB and p53-dependent cellular senescent phenotype in human fibroblasts. Mechanistically, RPL22/eL22 can interact with and inhibit CDK4-Cyclin D1 to decrease RB phosphorylation both in vitro and in cells. Briefly, we show that ribosome-free RPL22/eL22 causes a cell cycle arrest which could be relevant during situations of nucleolar stress such as cellular senescence or the response to cancer chemotherapy.
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http://dx.doi.org/10.1080/15384101.2019.1593708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464582PMC
April 2020

The senescence-associated secretory phenotype and its regulation.

Cytokine 2019 05 16;117:15-22. Epub 2019 Feb 16.

Department of Biochemistry and Molecular Medicine, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Québec H3C 3J7, Canada; CRCHUM, 900 Saint-Denis - Room R10.432, Montréal, QC H2X 0A9, Canada. Electronic address:

The senescence-associated secretory phenotype (SASP) defines the ability of senescent cells to express and secrete a variety of extracellular modulators that includes cytokines, chemokines, proteases, growth factors and bioactive lipids. The role of the SASP depends on the context. The SASP reinforces the senescent cell cycle arrest, stimulates the immune-mediated clearance of potentially tumorigenic cells, limits fibrosis and promotes wound healing and tissue regeneration. On the other hand, the SASP can mediate chronic inflammation and stimulate the growth and survival of tumor cells. The regulation of the SASP occurs at multiple levels including chromatin remodelling, activation of specific transcription factors such as C/EBP and NF-κB, control of mRNA translation and intracellular trafficking. Several SASP modulators have already been identified setting the stage for future research on their clinical applications.
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http://dx.doi.org/10.1016/j.cyto.2019.01.013DOI Listing
May 2019

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

Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway.

Nat Cell Biol 2018 07 25;20(7):789-799. Epub 2018 Jun 25.

Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Quebec, Canada.

Cellular senescence is a tumour suppressor programme characterized by a stable cell cycle arrest. Here we report that cellular senescence triggered by a variety of stimuli leads to diminished ribosome biogenesis and the accumulation of both rRNA precursors and ribosomal proteins. These defects were associated with reduced expression of several ribosome biogenesis factors, the knockdown of which was also sufficient to induce senescence. Genetic analysis revealed that Rb but not p53 was required for the senescence response to altered ribosome biogenesis. Mechanistically, the ribosomal protein S14 (RPS14 or uS11) accumulates in the soluble non-ribosomal fraction of senescent cells, where it binds and inhibits CDK4 (cyclin-dependent kinase 4). Overexpression of RPS14 is sufficient to inhibit Rb phosphorylation, inducing cell cycle arrest and senescence. Here we describe a mechanism for maintaining the senescent cell cycle arrest that may be relevant for cancer therapy, as well as biomarkers to identify senescent cells.
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http://dx.doi.org/10.1038/s41556-018-0127-yDOI Listing
July 2018
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