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Aurora-A induces cell survival and chemoresistance by activation of Akt through a p53-dependent manner in ovarian cancer cells

✍ Scribed by Hua Yang; Lili He; Patricia Kruk; Santo V. Nicosia; Jin Q. Cheng

Publisher
John Wiley and Sons
Year
2006
Tongue
French
Weight
719 KB
Volume
119
Category
Article
ISSN
0020-7136

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✦ Synopsis

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. © 2006 Wiley‐Liss, Inc.

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