Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in a PI3k-Akt-dependent manner

Moumen, Anice; Ieraci, Alessandro; Patanè, Salvatore; Solé, Carme; Comella, Joan X.; Dono, Rosanna; Maina, Flavio

doi:10.1002/hep.21604

Cited by 79 publications

(80 citation statements)

References 37 publications

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“…Akt/PI3K modulates the tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL)-and Fasmediated cell death by upregulating FLIP mRNA and/ or protein content in cancer cells, hepatocytes and endothelial cells (Panka et al, 2001;Nam et al, 2002Nam et al, , 2003Skurk et al, 2004;Alladina et al, 2005;Sta¨rck et al, 2005;Moriyama and Yonehara 2007;Moumen et al, 2007;Shim et al, 2007). Here we show that Akt activation inhibited CDDP-induced FLIP downregulation and apoptosis in wt-p53 chemosensitive ovarian cancer cells (OV2008 and A2780s).…”

Section: Discussionmentioning

confidence: 67%

Akt promotes chemoresistance in human ovarian cancer cells by modulating cisplatin-induced, p53-dependent ubiquitination of FLICE-like inhibitory protein

et al. 2009

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Although Akt is a determinant of cisplatin (cis-diaminedichloroplatinum (CDDP)) resistance in ovarian cancer cells, which is related in part to its inhibitory action on p53 activation, precisely how Akt confers CDDP resistance is unclear. In this study, we show that CDDP induced p53-dependent Fas-associated death domain-like interleukin-1b-converting enzyme (FLICE)-like inhibitory protein (FLIP) degradation in chemosensitive ovarian cancer cells but not their resistant counterparts. CDDP induced FLIP-p53-Itch interaction, colocalization and FLIP ubiquitination in chemosensitive but not chemoresistant ovarian cancer cells. Moreover, although activated Akt inhibited CDDP-induced FLIP degradation and apoptosis in sensitive cells, these responses were facilitated by dominant-negative Akt expression in chemoresistant cells. Inhibition of Akt function also facilitated p53-FLIP interaction and FLIP ubiquitination, which were attenuated by p53 silencing. These results suggest that Akt confers resistance, in part, by modulating CDDP-induced, p53-dependent FLIP ubiquitination. Understanding the precise etiology of chemoresistance may improve treatment for ovarian cancer.

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Section: Discussionmentioning

confidence: 67%

Akt promotes chemoresistance in human ovarian cancer cells by modulating cisplatin-induced, p53-dependent ubiquitination of FLICE-like inhibitory protein

et al. 2009

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“…For biochemical studies, cell extracts, immunoprecipitations, and western blots were performed as described previously. 14,15,44 For quantitative real-time PCR, total RNA was extracted with Trizol (Invitrogen), according to the manufacturer's instructions. Reverse transcription was performed with Superscript Reverse Transciptase II (Invitrogen), according to the manufacturer's instructions.…”

Section: Discussionmentioning

confidence: 99%

“…Survival assays and anchorage-independent growth assays were performed as previously described. 14,15,18 Data on biological assays are representative of three independent experiments performed in duplicate.…”

Section: Discussionmentioning

confidence: 99%

“…The Met-RTK and its ligand HGF have essential functions during embryogenesis and regenerative processes by regulating cell migration, survival, proliferation, and differentiation, similar to Met functions during the oncogenic processes, 4,[12][13][14][15][16][17] and effective Met antagonists have been identified. 4,18,19 Moreover, Met confers resistance to ErbB antagonists, as cancer cells use Met to maintain the RTK-driven oncogenic pathways active.…”

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confidence: 99%

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Abl interconnects oncogenic Met and p53 core pathways in cancer cells

et al. 2011

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The simplicity of BCR-ABL 'oncogene addiction' characterizing leukemia contrasts with the complexity of solid tumors where multiple 'core pathways', including receptor tyrosine kinases (RTKs) and p53, are often altered. This discrepancy illustrates the limited success of RTK antagonists in solid tumor treatment compared with the impact of Imatinib in BCR-ABL-dependent leukemia. Here, we identified c-Abl as a signaling node interconnecting Met-RTK and p53 core pathways, and showed that its inhibition impairs Met-dependent tumorigenesis. Met ensures cell survival through a new path in which c-Abl and p38-MAPK are employed to elicit p53 phosphorylation on Ser(392) and Mdm2 upregulation. We found a clinical correlation between activated Met, phospho-p53, and Mdm2 levels in human tumors, supporting the role of this path in tumorigenesis. Our findings introduce the concept that RTK-driven tumors may be therapeutically treated by hitting signaling nodes interconnecting core pathways. Moreover, they underline the importance of evaluating the relevance of c-Abl antagonists for combined therapies, based on the tumor signaling signature.Cell Death and Differentiation advance online publication, 1 April 2011; doi:10.1038/cdd.2011.23

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“…La voie PI3K, via l'activation d'Akt (protéine kinase B), joue aussi un rôle central dans la survie cellulaire induite par Met [18], tout comme la régulation de p53 par Abl et p38 [19]. Au cours des années 2000, différents mécanismes de régulation négative du récepteur Met ont été mis en évidence.…”

Section: Revuesunclassified