Papers by Christèle Desbois-mouthon
The American Journal of Pathology, 2005
Supported by the Association pour la Recherche sur le Cancer (to M.B.) and the Ligue Nationale Co... more Supported by the Association pour la Recherche sur le Cancer (to M.B.) and the Ligue Nationale Contre le Cancer (to E.B.).
Gastroentérologie Clinique et Biologique, 2006
Experimental Cell Research, 2004
Lithium exerts neuroprotective actions that involve the inhibition of glycogen synthase kinase-3h... more Lithium exerts neuroprotective actions that involve the inhibition of glycogen synthase kinase-3h (GSK-3h). Otherwise, recent studies suggest that sustained GSK-3h inhibition is a hallmark of tumorigenesis. In this context, the present study was undertaken to examine whether lithium modulated cancer cell sensitivity to apoptosis induced by chemotherapy agents. We observed that, in different human cancer cell lines, lithium significantly reduced etoposide-and camptothecin-induced apoptosis. In HepG2 cells, lithium repressed drug induction of CD95 expression and clustering at the cell surface as well as caspase-8 activation. Lithium acted through deregulation of GSK-3h signaling since (1) it provoked a rapid and sustained phosphorylation of GSK-3h on the inhibitory serine 9 residue; (2) the GSK-3h inhibitor SB-415286 mimicked lithium effects by repressing drug-induced apoptosis and CD95 membrane expression; and (3) lithium promoted the disruption of nuclear GSK-3h/p53 complexes. Moreover, the overexpression of an inactivated GSK-3h mutant counteracted the stimulatory effects of etoposide and camptothecin on a luciferase reporter plasmid driven by a p53-responsive sequence from the CD95 gene. In conclusion, we provide the first evidence that lithium confers resistance to apoptosis in cancer cells through GSK-3h inhibition and subsequent repression of CD95 gene expression. Our study also highlights the concerted action of GSK-3h and p53 on CD95 gene expression. D
Hepatology, 2005
Epidermal growth factor receptor (EGFR) binds transforming growth factor ␣ (TGF-␣) which is mitog... more Epidermal growth factor receptor (EGFR) binds transforming growth factor ␣ (TGF-␣) which is mitogenic for hepatocytes. Diverse lines of evidence suggest that activation of the TGF-␣ /EGFR pathway contributes to hepatocellular carcinoma (HCC) formation. Herein, we developed an experimental model of cirrhosis giving rise to HCC and tested the antitumoral effect of gefitinib, a selective EGFR tyrosine kinase inhibitor, in this model. Rats received weekly intraperitoneal injections of diethylnitrosamine (DEN) followed by a 2-week wash-out period that caused cirrhosis in 14 weeks and multifocal HCC in 18 weeks. Hepatocyte proliferation was increased in diseased tissue at 14 weeks compared with control liver and at even higher levels in HCC nodules compared with surrounding diseased tissues at 18 weeks. Increased proliferation was paralleled by upregulation of TGF-␣ messenger RNA expression. A group of DEN-treated rats received daily intraperitoneal injections of gefitinib between weeks 12 and 18. In rats treated with gefitinib, the number of HCC nodules was significantly lower than in untreated rats (18.1 ؎ 2.4 vs. 3.7 ؎ 0.45; P < .05), while EGFR was activated to a lesser extent in the diseased and tumoral tissues of these animals compared with untreated rats. HCC nodules from both untreated and gefitinib-treated animals displayed insulin-like growth factor 2 overexpression that contributed to tumor formation in treated animals. In conclusion, the blockade of EGFR activity by gefitinib has an antitumoral effect on the development of HCC in DEN-exposed rats, suggesting that it may provide benefit for the chemoprevention of HCC. (HEPATOLOGY 2005;41:307-314.)
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Papers by Christèle Desbois-mouthon