4.7 Article Publication with Expression of Concern

Aurora-A induces cell survival and chemoresistance by activation of Akt through a p53-dependent manner in ovarian cancer cells (Publication with Expression of Concern. See vol. 144, 2019)

期刊

INTERNATIONAL JOURNAL OF CANCER
卷 119, 期 10, 页码 2304-2312

出版社

WILEY
DOI: 10.1002/ijc.22154

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aurora-A; Akt; p53; API-2; chemoresistance; ovarian cancer; kinase; apoptosis; cisplatin

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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. (c) 2006 Wiley-Liss. Inc.

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