Abstract 1042: Activation of AKT negates the pro-apoptotic function of Par-4 in castration resistant prostate cancer cells

Abstract

Abstract Activation of AKT signaling pathway is a common aberrations in advanced castration resistant prostate cancer (CRPC). PTEN, a tumor suppressor is known to negatively regulate AKT function, however, in most cancer deletion or mutation of PTEN facilitates AKT mediated survival signaling in most cancer types. In this study, we have determined the clinical and pathological significance of AKT signaling in CaP tissues and CRPC cell lines. AKT and pAKT (ser473) were measured in prostate tumor tissues (Normal = 23, Grade I=13, Grade II-24 and Grade III=26) by immunohistochemistry analysis. Phosphorylated AKT is significantly higher in tumors (Grades-I, II and III) as compared to the normal/hyperplastic tissues; however, there no significant differences were seen in AKT expression between normal and tumor tissues. In CRPC cell lines, stable expression of AKT increases proliferation, epithelial mesenchymal transition and angiogenesis in cancer cells. Injection of over expressed AKT, CRPC cells resulted in tumor growth in athymic mice as compared to vector cells. We observed AKT tumors grow rapidly, are larger in size and showed 100% tumorigenecity as compared to the control tumors (40%), which had slow growth, as well as small tumors. Interestingly, subcutaneous injection of AKT/CRPC cells in athymic mice showed hyperplasia in anterior and a ventral lateral lobe of the prostate, which was absent in control tumors. We also found that AKT tumors are highly vascularized than the control tumors; however no micrometastasis were observed in our H &E analysis. Our in vitro studies have revealed that treatment of Withaferin-A, an herbal compound inhibits AKT activation and up regulates Par-4 mediated apoptosis by activating caspase cascades in CRPC cells. In addition, WA overcomes AKT induced resistance in CRPC cells and restores Par-4 function that resulted in growth inhibition in AKT over expressed CRPC (DU-145 and C4-2B) cells. Similarly, oral administration of WA (4mg/kg) significantly inhibited the growth of both control and AKT over expressed tumors (P< 0.001). Currently, we are observing tumor regrowth after stopping the WA treatment and immunohistochemistry analysis to confirm AKT mediated pro-survival signaling and EMT markers in the tumor tissues. These finding suggest WA could be a potent agent which overrides AKT mediated pro-survival and EMT signaling in CRPC cells, hence it can be used as a chemopreventive and/or chemotherapeutic agent for highly aggressive and metastatic prostate cancer. Note: This abstract was not presented at the meeting. Citation Format: Trinath P. Das, Suman Suman, Chendil Damodaran. Activation of AKT negates the pro-apoptotic function of Par-4 in castration resistant prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1042. doi:10.1158/1538-7445.AM2014-1042