E2F1 regulates an apoptotic response to AKT inhibition in prostate cancer

Abstract

The progression of prostate cancer is associated with a selective growth advantage under androgen-depleted conditions, which is accompanied by notorious resistance to most available therapies. Recently geraniol, a naturally occurring monoterpene, has been reported to possess chemotherapeutic potentials against colon and pancreatic cancers. However, the mechanisms of the geraniol action against prostate cancer are poorly understood. In this study, I investigated the anticancer activity of geraniol against prostate cancer. First, in part Ⅰ, I found that geraniol induces G1 arrest and apoptosis in PC-3 androgen-independent prostate cancer cells. Xenograft model experiments demonstrate that geraniol reduces tumor volumes and weights. In addition, I showed that geraniol increases the sensitivity of prostate cancer to various chemotherapeutic agents in cultured cells and then demonstrate that the combination of sub-optimal dose of geraniol and docetaxel noticeably suppresses prostate cancer growth in tumor xenograft mice. Next, I investigated the molecular mechanisms of geraniol-induced cell death in PC-3 prostate cancer cells. Among the examined structurally and functionally similar monoterpenes, geraniol specifically induced apoptosis and autophagy. Although independent processes, apoptosis and autophagy acted as cooperative partners to elicit geraniol-induced cell death in PC-3 cells. At a molecular level, geraniol inhibited AKT signaling and activated AMPK signaling, resulting in mTOR inhibition. Combined treatment of AKT inhibitor and AMPK activator markedly suppressed cell growth compared to either treatment alone. My findings provide insight into future investigations that are aimed at elucidating the role of apoptosis and autophagy in prostate cancer therapy and at developing the anticancer strategies deregulating AKT/mTOR pathway. AKT/mTOR pathway has been reported to possess chemotherapeutic potentials in most of cancers, since PTEN loss and decreased expression of androgen receptor provide activated survival pathway, which confers growth advantages by achieving self-sufficiency in growth signals. However, AKT/mTOR pathway is associated with receptor tyrosine kinase family by negative feedback network. Recent several reports showed that inhibition of AKT/mTOR pathway relieves the negative feedback loop of receptor tyrosine kinase family. In addition, AKT knockdown did not induce apoptosis, thereby it did not promote profound cell death as a therapeutic approach. Therefore, in part Ⅱ, I used network analysis to assume molecule, which induces synthetic lethality with AKT. As a result of network modeling, I found that E2F1 as a critical hub is down-regulated by high dose of AKT inhibitors. This dose causes significant cell death. In addition I found that inhibition of E2F1 is associated with inhibition of receptor tyrosine kinase family expression and activity. Consequently, I suggest that, in CRPC cells in which achieve growth advantage through hyper-activated oncogenic pathway, combined inhibition of AKT and E2F1 is more effective than either alone.