PI3K/Akt signaling pathway in human ovarian cancer

Ovarian cancer remains the most fatal gynecologic malignancy in women in the United States, and the development of drug resistance constitutes a major obstacle to the cure of even sensitive tumors.; The studies that I have accomplished show that PI3K/Akt signaling pathway plays a critical role in ovarian oncogenesis. I have demonstrated frequent activation and/or overexpression of PI3K and AKT2 in human primary ovarian cancer. Moreover, I have shown that PI3K inhibitors induce programmed cell death in ovarian cancer cell with elevated levels of AKT2 kinase activity, suggesting PI3K/AKT2 is a potential chemotherapeutic target for ovarian cancer intervention.; Since many ovarian tumors are believed to be the result of repeated exposure to stress and cytokines during repetitive ovulation. I have demonstrated that AKT2 is activated by stresses including UV and TNFα in a PI3K-dependent manner and that the activated AKT2 protects stress-induced ovarian cancer cell death by inhibiting c-Jun N-terminal kinase (JNK) and p38 activity through activation of NFκB pathway. AKT2 phosphorylation of IKKα on Ser23 is critical for the activation of NFκB pathway and the inhibition of JNK/p38 activity. In addition, I have recently shown that activation of AKT2 contributes to cisplatin resistance in ovarian cancer cell through inhibition of JNK and p38 pathway and Bax conformation change. AKT2 phosphorylates and interacts with apoptosis stimulating kinase-1 (ASK1) and thereafter JNK, p38 and Bax. Further, I have demonstrated that activation of JNK and p38 is required for cisplatin-induced Bax conformation change. Taken collectively, these data provide valuable information regarding the molecular mechanism of PI3K/AKT2 pathway in ovarian carcinogenesis and drug resistance.; In attempt to identify Akt interaction protein(s), I have performed yeast two-hybrid screening and cloned an Akt-binding protein, named APαB. I have shown that SH3 domains of APαB function as docking sites for Akt and p21 activated kinase 1 (PAK1). APαB is phosphorylated by Akt in vitro and in vivo and mediates Akt-induced PAK1 activation, in addition to directly inducing PAK1 kinase activity. As a result, APαB enhances Akt and PAK1-induced Bad phosphorylation and cell survival. These data indicate that APαB plays a pivotal role in Akt and PAK1 signaling.