Abstract 3213: Selective killing of advanced prostate cancer cells by targeting the Warburg effect and autophagy

Abstract

Abstract Mutations of multiple tumor suppressor genes, such as PTEN and p53, have been proposed to play important roles in the development of prostate cancer. Loss of one allele of PTEN occurs in 70-80% of human primary prostate tumors and homozygous inactivation of PTEN is associated with advanced disease. Similarly, p53 is found completely lost or mutated almost exclusively in advanced human prostate cancer. Thus, selective killing of prostate cancer cells harboring mutations of PTEN and p53 may prove to be a promising strategy for the treatment of advanced prostate cancer. The Warburg effect of aerobic glycolysis has now been generally accepted as a key metabolic hallmark of cancer. In this study, we investigated the molecular target leading to the Warburg effect in the growth and aggressiveness of prostate cancer cells harboring inactivation of PTEN and p53 and delineated the underlying mechanism. We identified that expression of hexokinase II (HK2), an enzyme involved in the first step of glycolysis, is preferentially elevated in human prostate cancer cells bearing mutations of both PTEN and p53 (PC3). Functional studies demonstrated that HK2 expression is crucial for the Warburg effect in PC3 cells and knockdown of HK2 inhibits tumor growth in PC3 xenograft mouse model. These novel findings prompted us to test whether 2-de-oxyglucose (2-DG), an inhibitor of HK2, could potentially suppress prostate cancer growth by targeting the Warburg effect. We found that an induction of AMPK-dependent autophagy prevents cancer cells from apoptosis upon 2-DG treatment, thereby limiting therapeutic efficacy on prostate cancer in vivo. Consistent with cell survival function of autophagy, its inhibition by chloroquine (a small molecule inhibitor of autophagy) or individual knockdown of the essential genes involved in autophagy (Atg5, Atg7, Beclin1, and ULK1) induced massive cell death when combined with 2-DG. This cell death can be rescued by overexpression of anti-apoptotic protein Bcl-2 or downregulation of pro-apoptotic protein Bax in PC3. More importantly, we demonstrated that combination of chloroquine and 2-DG could specifically kill prostate cancer cells, leaving normal prostate epithelial cells untouched. This specificity is due to the preferential induction of HK2 through the activated Rictor-AKT-mTOR pathway in cancer cells. Finally, combination of chloroquine and 2-DG caused synthetic lethality in prostate cancer cells and effectively suppressed tumor growth in PC3 xenograft mouse model. Towards therapeutic translation, we have observed that expression of HK2 by staining primary human prostate tumor samples with HK2 antibodies correlated with the stages of prostate cancer. Given our findings, we therefore propose that targeting the Warburg effect and autophagy pathways may serve as an effective and selective treatment for patients with advanced prostate cancer, in particular those with PTEN and p53 mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3213. doi:1538-7445.AM2012-3213