Abstract
Many studies involving patients with cisplatin-resistant ovarian cancer have shown that AKT activation leads to inhibition of apoptosis. The aim of this study was to examine the potential involvement of the Bcl-2 family proteins in AKT-regulated cell survival in response to cisplatin treatment. Cisplatin-sensitive (PEO1) and cisplatin-resistant (PEO4) cells were taken from ascites of patients with ovarian cancer before cisplatin treatment and after development of chemoresistance. It was found that cisplatin treatment activated the AKT signaling pathway and promoted cell proliferation in cisplatin-resistant EOC cells. When AKT was transfected into nucleus of cisplatin-resistant ovarian cancer cells, DNA-PK was phosphorylated at S473. The activated AKT (pAKT-S473) in these cells inhibited the death signal induced by cisplatin thereby inhibiting cisplatin-mediated apoptosis. Results from this study showed that the combination of cisplatin, DNA-PK inhibitor NU7441, and AKT inhibitor TCN can overcome drug resistance, increase apoptosis, and re-sensitize PEO4 cells to cisplatin treatment. A decrease in apoptotic activity was seen in PEO4 cells when Bad was downregulated by siRNA, which indicated that Bad promotes apoptosis in PEO4 cells. Use of the Bcl-2 inhibitor ABT-737 showed that ABT-737 binds to Bcl-2 but not Mcl-1 and releases Bax/Bak which leads to cell apoptosis. The combination of ABT-737 and cisplatin leads to a significant increase in the death of PEO1 and PEO4 cells. All together, these results indicate that Bcl-2 family proteins are regulators of drug resistance. The combination of cisplatin and Bcl-2 family protein inhibitor could be a strategy for the treatment of cisplatin-resistant ovarian cancer.
Highlights
Ovarian cancer is a devastating malignancy, causing more deaths in the female US population compared to any other gynecologic cancer [1]
These results showed no clear role for caspase-8 or -9 in apoptosis in the response of PEO1 and PEO4 cells to cisplatin, they are downstream mediators of apoptosis and may be activated following treatment for a longer period (e.g. 24 hrs)
Bcl-2 family proteins are key modulators of the intrinsic mitochondrial-mediated apoptotic pathway and regulation of the activity of some members within this family have been associated with AKT phosphorylation and chemosensitivity in Epithelial ovarian cancer (EOC) [2, 8, 9]
Summary
Ovarian cancer is a devastating malignancy, causing more deaths in the female US population compared to any other gynecologic cancer [1]. 80% of EOC patients will soon relapse after first-line chemotherapy [3] This is in part due to the difficulty in diagnosis and treatment, the rising concern of drug resistance. The median progression-free survival (PFS) is 18 months before most of these patients relapse [2] Those with tumors that progress during or recur within 6 months of treatment are considered platinum-resistant [3]. Treatment failure is thought to be attributed to drug resistance in over 90% of cases with metastatic malignancy [2]. It can arise from multiple factors such as pharmacokinetic interactions, tumor micro-environment, and most likely, cancer-cell-specific abnormalities [2]. There is a dire need to better elucidate the mechanisms behind ovarian cancer drug resistance and how to overcome them
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