title: Aurora-A induces cell survival and chemoresistance by activation of Akt through a p53-dependent manner in ovarian cancer cells.
abstract: Aurora-A is frequently altered in epithelial malignancies. Overexpressing Aurora-A induces centrosome amplification and G2/M cell cycle progression. We have previously shown elevated level of Aurora-A in ovarian cancer and activation of telomerase by Aurora-A in human mammary and ovarian epithelia. Here we report that Aurora-A protects ovarian cancer cells from apoptosis induced by chemotherapeutic agent and activates Akt pathway in a p53-dependent manner. Ectopic expression of Aurora-A renders cells resistant to cisplatin (CDDP), etoposide and paclitaxel-induced apoptosis and stimulates Akt1 and Akt2 activity in wild-type p53 but not p53-null ovarian cancer cells. Aurora-A inhibits cytochrome C release and Bax conformational change induced by CDDP. Knockdown of Aurora-A by RNAi sensitizes cells to CDDP-induced apoptosis and decreases phospho-Akt level in wild-type p53 cells. Reintroduction of p53 decreases Akt1 and Akt2 activation and restores CDDP sensitivity in p53-null but not p53-null-Aurora-A cells. Inhibition of Akt by small molecule inhibitor, API-2, overcomes the effects of Aurora-A-on cell survival and Bax mitochondrial translocation. Taken collectively, these data indicate that Aurora-A activates Akt and induces chemoresistance in a p53-dependent manner and that inhibition of Akt may be an effective means of overcoming Aurora-A-associated chemoresistance in ovarian cancer cells expressing wild-type p53.
authors.affiliation: Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, 33612, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Lili
authors.initials: L
authors.lastname: He
authors.forename: Patricia
authors.initials: P
authors.lastname: Kruk
authors.forename: Santo V
authors.initials: SV
authors.lastname: Nicosia
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel; D002945:Cisplatin