Abstract
Ovarian cancer is the most common cause of death from gynecologic malignancy. Deregulation of p53 and/or p73-associated apoptotic pathways contribute to the platinum-based resistance in ovarian cancer. NOXA, a pro-apoptotic BH3-only protein, is identified as a transcription target of p53 and/or p73. In this study, we found that genetic variants of Bcl-2 proteins exist among cisplatin-sensitive and -resistant ovarian cancer cells, and the responses of NOXA and Bax to cisplatin are regulated mainly by p53. We further evaluated the effect of NOXA on cisplatin. NOXA induced apoptosis and sensitized A2780s and SKOV3 cells to cisplatin in vitro and in vivo. The effects were mediated by elevated Bax expression, enhanced caspase activation, release of Cyt C and Smac into the cytosol. Furthermore, gene silencing of Bax or Smac significantly attenuated NOXA and/or cisplatin-induced apoptosis in chemosensitive A2780s cells, whereas overexpression of Bax or addition of Smac-N7 peptide significantly increased NOXA and/or cisplatin-induced apoptosis in chemoresistant SKOV3 cells. To our knowledge, these data suggest a new mechanism by which NOXA chemosensitized ovarian cancer cells to cisplatin by inducing alterations in the Bax/Smac axis. Taken together, our findings show that NOXA is potentially useful as a chemosensitizer in ovarian cancer therapy.
Highlights
Ovarian cancer is the most common cause of death from gynecologic malignancy [1]
We found that NOXA induces apoptosis independently of p53 in both A2780s and SKOV3 cells, and that elevated expression of NOXA can enhance sensitivity of ovarian cancer cells to cisplatin through the alterations in the Bax/Smac axis
Western blotting analysis showed that cisplatin-sensitive (A2780s, IGROV1 and OAW42) cell lines express relatively low endogenous levels of Bcl-2, Bcl-xL and Mcl-1 while cisplatinresistant (A2780cp, OVCAR-3 and SKOV3) cell lines were on the contrary
Summary
Ovarian cancer is the most common cause of death from gynecologic malignancy [1]. there are some improvements, the long-term survival remains poor due to dose-dependent toxicity, eventual tumor recurrence and emergence of drugresistant disease. Recent reports have shown that p73, a member of p53 family proteins, is a key regulator of apoptosis susceptibility to cisplatin (Cis) in A2780 ovarian cancer cells [6,7], and that p73-dependent transcriptional program is an important contributor to the chemosensitivity pathway in BRCA1-deficient ovarian carcinoma cells [8], indicating some mechanisms affecting p73 expressions and functions may contribute to the development of resistance to cisplatin-induced apoptosis in ovarian cancer cells [7] All these observations suggest that deregulation of p53-dependent and/or p73-associated apoptotic pathways may contribute to the platinum-based resistance in ovarian cancer. Restoration of the p53 and/or p73 pathway by activating themselves or their downstream targets may be an attractive avenue to improve efficacy of anticancer therapies
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