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Akt promotes cisplatin resistance in human ovarian cancer cells through inhibition of p53 phosphorylation and nuclear function
Author(s) -
Fraser Michael,
Bai Tao,
Tsang Benjamin K.
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23086
Subject(s) - cisplatin , puma , protein kinase b , apoptosis , downregulation and upregulation , cancer research , phosphorylation , ovarian cancer , pi3k/akt/mtor pathway , biology , cancer cell , kinase , cancer , microbiology and biotechnology , chemotherapy , biochemistry , genetics , gene
Resistance to cisplatin‐based chemotherapy is a major cause of treatment failure in human ovarian cancer. Wild‐type TP53 status is often, but not always, associated with cisplatin sensitivity, suggesting that additional factors may be involved. Overexpression/activation of the phosphatidylinositol‐3‐kinase/Akt pathway is commonly observed in ovarian cancer, and Akt activation is a determinant of chemoresistance in ovarian cancer cells, an effect that may be due, in part, to its inhibitory actions on p53‐dependent apoptosis. To that end, we examined the role and regulation of p53 in chemosensitive ovarian cancer cells, as well as in their chemoresistant counterparts, and investigated if and how Akt influences this pathway. Cisplatin induced apoptosis in chemosensitive, but not chemoresistant cells, and this was inhibited by downregulation of p53. Cisplatin upregulated PUMA in a p53‐dependent manner, and the presence of PUMA was necessary, but not sufficient for cisplatin‐induced apoptosis. p53 was phosphorylated on numerous N‐terminal residues, including Ser15, Ser20, in response to cisplatin in chemosensitive, but not chemoresistant cells. Furthermore, activation of Akt inhibited the cisplatin‐induced upregulation of PUMA, and suppressed cisplatin‐induced p53 phosphorylation, while inhibition of Akt increased total and phospho‐p53 contents and sensitized p53 wild‐type, chemoresistant cells to cisplatin‐induced apoptosis. Finally, mutation of Ser15 and/or Ser20, but not of Ser37, to alanine significantly attenuated the ability of p53 to facilitate CDDP‐induced apoptosis, and this was independent of PUMA expression. These results support the hypothesis that p53 is a determinant of CDDP sensitivity, and suggest that Akt contributes to chemoresistance, in part, by attenuating p53‐mediated PUMA upregulation and phosphorylation of p53, which are essential, but independent determinants of sensitivity to CDDP‐induced apoptosis. © 2007 Wiley‐Liss, Inc.