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

• Published in: Oncogene Vol. 29; no. 1; pp. 11 - 25
• Main Authors: Abedini, M R, Muller, E J, Bergeron, R, Gray, D A, Tsang, B K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.01.2010; Nature Publishing Group
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; CASP8 and FADD-Like Apoptosis Regulating Protein - genetics; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; Cell Biology; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Cisplatin - pharmacology; Drug resistance; Drug Resistance, Neoplasm; Enzymes; Female; Female genital diseases; Fundamental and applied biological sciences. Psychology; Genetics; Gynecology. Andrology. Obstetrics; Human Genetics; Humans; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Microscopy, Confocal; Molecular and cellular biology; Oncology; original-article; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Protein Binding - drug effects; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA Interference; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - drug effects; chemoresistance; Akt; ovarian cancer; FLIP; p53; Antineoplastic agent; Human; Ovary cancer; Akt protein kinase; Malignant tumor; Carcinogenesis; Cisplatin; Protein; Female genital diseases; Ovarian diseases; TP53 Gene; Cancer; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.300

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-1β-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.