Protein Kinase G-Iα Hyperactivation and VASP Phosphorylation in Promoting Ovarian Cancer Cell Migration and Platinum Resistance

Platinum-based drugs such as cisplatin (cis-diammine-dichloro-platinum, also commonly known as CDDP) have dominated the drug therapy of ovarian cancer during the past three decades [1]. Cisplatin interacts with DNA to form intrastrand crosslink adducts, and its mo‐ lecular mechanism involves regulation of p53 and the mitogen-activated protein kinase (MAPK) signaling pathway [2]. The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is crucial for regulation of survival and for progression and chemoresistance in ovarian cancer, leading to the development of new chemotherapeutic inhibitors targeting the PI3K/Akt pathway and the downstream serine/threonine protein kinase mTOR. [3]. In‐ hibition of PI3K pathway signaling using PI3K or mTOR inhibitors has been shown to sensi‐ tize ovarian cancer cell lines to the apoptosis-inducing effect of platinum compounds [4, 5]. In addition, activation of the PI3K/Akt/mTOR pathway in ovarian cancer cell lines contrib‐ utes to cisplatin resistance [6]. The anti-apoptotic, pro-angiogenic effects of PI3K/Akt/mTOR may be mediated, at least in part, through a downstream signaling pathway involving en‐ dogenous endothelial-form nitric oxide synthase (eNOS, also called NOS3), and subsequent‐ ly soluble guanylyl cyclase (sGC) and protein kinase G (PKG). Studies have shown that Akt activates eNOS by phosphorylating human eNOS at Ser1177 (equivalent to bovine eNOS at Ser1179), leading to an increase in nitric oxide (NO) production in endothelial cells [7, 8]. In the cases of vascular endothelial growth factor (VEGF) [9, 10], sphingosine 1-phosphate [11, 12], and estrogen [13, 14], there are vast evidences suggesting PI3K-activation of Akt is re‐ sponsible for regulating the phosphorylation and activation of eNOS. In bovine aortic endo‐ thelial cells, eNOS co-immunoprecipitates with Akt, indicating that the two enzymes associate in vivo, and Akt directly activates eNOS, increasing eNOS activity by 15-20 fold