Akt is the focal point of a number of signaling pathways that regulate cell survival and tumor progression. Akt interacts with, and modifies via phosphorylation, many substrates involved in these cellular events. Owing to its anti-apoptotic properties, Akt plays a key role in promoting human cancer. Thus, the identification of molecules that interact with Akt may lead to a better understanding of the role of Akt in various local signaling networks and enable the development of strategies for specifically blocking signaling pathways involved in cancer development and progression. Par-4 is a leucine zipper domain protein that, when ectopically expressed, induces apoptosis in cancer cells but not in normal or immortalized cells. Apoptosis by ectopic Par-4 occurs by inhibition of NF-kappaB activity. As cancer cells contain reasonable levels of endogenous Par-4, we sought to determine whether Par-4 exists in an inactive form. Our Preliminary Studies reveal that Akt1 binds and inactivates endogenous Par-4, rendering it ineffective in apoptosis-induction. Moreover, inactivation of Akt1 releases Par-4 to induce apoptosis, implying that endogenous Par-4 is functionally active in the absence of Akt1. In view of the pro-survival functions of Akt1 and the pro-apoptotic functions of Par-4, the objective of this proposal is to study the molecular basis and functional relevance of the interaction between Akt1 and Par-4 in prostate cancer cell survival and tumor progression. Toward this end, we propose the following specific aims:
Aim 1, elucidate the molecular basis for the isoform-specific effects of Akt on Par-4;
Aim 2, determine the mechanism for cytoplasmic retention and inactivation of Par-4 by Akt1;
and Aim 3, determine the downstream effects and functional relevance of Par-4 inhibition by Akt1 in tumor growth. Because PTEN loss is a well defined genetic lesion that elevates Akt activity and neutralizes the apoptotic pathway in the prostate, and contributes to prostate tumors in mouse models, this study will focus on the prostate cancer cell background to study the Akt1-Par-4 interaction. However, as the Akt1-Par-4 interaction occurs in diverse tumor cell types, we anticipate that the findings of this study will have broad implications in cancer. The findings will be further developed in future studies to design therapeutic strategies that can prevent Par-4 binding to Akt1 and induce apoptosis and tumor growth regression.
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