Abstract
Cisplatin and its analogues have been widely used for treatment of human cancer. However, most patients eventually develop resistance to treatment through a mechanism that remains obscure. Previously, we found that AKT2 is frequently overexpressed and/or activated in human ovarian and breast cancers. Here we demonstrate that constitutively active AKT2 renders cisplatin-sensitive A2780S ovarian cancer cells resistant to cisplatin, whereas phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 sensitizes A2780S and cisplatin-resistant A2780CP cells to cisplatin-induced apoptosis through regulation of the ASK1/JNK/p38 pathway. AKT2 interacts with and phosphorylates ASK1 at Ser-83 resulting in inhibition of its kinase activity. Accordingly, activated AKT2 blocked signaling down-stream of ASK1, including activation of JNK and p38 and the conversion of Bax to its active conformation. Expression of nonphosphorylatable ASK1-S83A overrode the AKT2-inhibited JNK/p38 activity and Bax conformational changes, whereas phosphomimic ASK1-S83D inhibited the effects of cisplatin on JNK/p38 and Bax. Cisplatin-induced Bax conformation change was inhibited by inhibitors or dominant negative forms of JNK and p38. In conclusion, our data indicate that AKT2 inhibits cisplatin-induced JNK/p38 and Bax activation through phosphorylation of ASK1 and thus, plays an important role in chemoresistance. Further, regulation of the ASK1/JNK/p38/Bax pathway by AKT2 provides a new mechanism contributing to its antiapoptotic effects.
Highlights
Cisplatin and its analogues have been widely used for ing decreased cellular detoxication [3, 4], increased DNA repair treatment of human cancer
We show that activation of AKT2 significantly increases the resistance of ovarian cancer cells to cisplatin
Studies using dominant negative mutants of JNK and p38 and specific pharmacological inhibitors have shown that activation of JNK and/or p38 is necessary for stress or chemotherapeutic drug-induced apoptosis [38, 40]
Summary
Cisplatin and its analogues have been widely used for ing decreased cellular detoxication [3, 4], increased DNA repair treatment of human cancer. We show that AKT2 activity promotes resistance to cisplatin-induced apoptosis in A2780S ovarian cancer cells through the inhibition of the ASK1/JNK/p38 pathway. Activation of AKT2 Renders Cisplatin-sensitive Cells Resistant to Cisplatin and Inhibits Cisplatin-induced Bax Conformational Change—We have shown previously [18, 34] frequent activation of AKT2 kinase in human ovarian and breast cancers.
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