Abstract 4949: Essential role of arachidonic acid metabolism in prostate cancer stem cell survival

Abstract

Abstract Background: Cancer stem cells (CSC) are rare group of neoplastic cells with features that include, self-renewal, pluripotency and tumorigenicity, and are thought to be responsible for tumor recurrence and metastasis. Thus, a lot of excitement surrounds the idea of going right to the root of the tumor and target the stem cells to eradicate cancer permanently. A hierarchically organized CSC model in prostate cancer is evident with CD44 (+), CD133 (+) subpopulations isolated from human prostate tumors. While most therapies are directed to the fast-growing tumor mass made of differentiated cells, they cannot target the relatively slow-dividing and resistant cancer stem cells, which may underlie as a mechanism of why the cancer is not permanently eradicated with standard chemotherapy. Thus, an important challenge is to find measures to eliminate the CSCs, which by definition, will stop tumor growth and prevent recurrence. However, knowledge about molecular features critical for prostate cancer stem cells (PCSC) is meager. Thus, we wanted to examine the role of arachidonate 5-lipoxygenase (ALOX5) which plays critical role in the survival of cancer (but not of normal) cells, in the biology of PCSC. Methods: Using an established, clinically-relevant in vitro model of human PCSCs which express both pluripotency markers (Nanog, c-Myc, Sox2) and tumor-progenitor markers (CD44, CD133, ALDH1), we interrogated the role of a fatty acid metabolic pathway in stem cell vulnerability. Especially, our goal was to characterize the effects of targeting ALOX5 to see whether it could be a new target to eliminate PCSCs. Results: Inhibition of ALOX5 by shRNA or MK591 dramatically decreased the protein levels of Nanog and c-Myc, suggesting a role for ALOX5 in prostate cancer stemness. Moreover, ALOX5 inhibition was found to selectively kill PCSCs (but not normal stem cells) by inducing apoptosis via inhibition of survivin, cyclin D1 and CDK4, and activation of c-Jun N-terminal Kinase and caspase 3, suggesting an essential role of ALOX5 in the survival of PCSC. Interestingly, non-cancer parenchyma body cells, including normal stem cells, do not express ALOX5 (presumably because of promoter hypermethylation) and are not affected by ALOX5 inhibitors. Conclusion: Our findings indicate that ALOX5 plays a causal role in maintaining prostate cancer stemness by regulating Nanog and c-Myc oncogenes, and suggest that an effective, long-lasting therapy of prostate cancer may be possible by targeting ALOX5 to kill and eliminate PCSCs to block prostate tumor growth and prevent recurrence. Citation Format: Jitender Monga, Brendan Carney, Sejal Patil, Jagadananda Ghosh. Essential role of arachidonic acid metabolism in prostate cancer stem cell survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4949.