Abstract 2437: Novel metabolic adaptations support proliferation of African American prostate cancer cells under hypoxia

Abstract

Abstract Hypoxia in prostate cancer (PCa) selects for aggressive clones and causes treatment failure, metastatic progression and mortality. Despite the key role of hypoxia in prostate carcinogenesis, little is known about the specific effect of hypoxia in African Americans, a race that faces a serious PCa-related health disparity with the highest incidence and mortality rate. We hypothesize that metabolic adaptation to hypoxia is one mechanism that contributes to PCa aggressiveness in African Americans. Therefore, in the present work we focused on the metabolic adaptations, both in vitro and in vivo, contributing to proliferation of African American PCa cells under hypoxic conditions. PCa cells from men of African American ancestry (E006AA-hT, MDA PCa 2b, WFCB17 and 22Rv1) showed proliferation and significantly higher clonogenicity under hypoxia (1% O2) compared to normoxia. In contrast, Caucasian PCa cells (LNCaP and PC3) showed significant growth inhibition under similar hypoxic condition. The proliferation under hypoxia in African American PCa cells was associated with higher beta-oxidation of lipids as measured by malate response in Oroboros Oxygraph system. In addition, [18F]-fluoro-4-thia-oleate ([18F]-FTO) uptake in African American PCa cells under hypoxia was more than 2-fold higher (p <0.001) compared to normoxic cells, confirming higher beta-oxidation in hypoxic PCa cells. Furthermore, African American PCa cells showed more than 2-fold (p <0.001) higher uptake of [11C]-acetate under hypoxia, suggesting increased fatty acid synthesis during hypoxia in African American PCa cells. This suggests that African American PCa cells may increase fatty acid synthesis under hypoxia to provide metabolic fuel. Fatty acid oxidation is associated with mitochondrial metabolism; accordingly, we observed higher oxidative phosphorylation, complex II activity and expression under hypoxia in African American PCa cells. Importantly, treatment with complex II inhibitor Atpenin A5 (1-2 microM) strongly reduced the clonogenicity (51%-79%, p <0.0001) of African American PCa cells under hypoxia. In vivo, mPET/CT imaging using [18F]-FTO and [18F]-fluoromisonidazole as PET tracers showed greater tumor uptake of both tracers in 22Rv1 tumors in male athymic nude mice, suggesting that hypoxia and fatty acid oxidation are associated with African American PCa growth. Furthermore, analyses of 22Rv1 tumor tissues by confocal microscopy showed higher level of carnitine palmitoyltransferase 1 (a key regulator of β-oxidation) and succinate dehydrogenase B (a subunit of complex II) in hypoxic areas (pimonidazole+) of the tumor. Taken together, these data demonstrate that proliferation of African American PCa cells under hypoxia is supported by high lipid beta-oxidation, lipid synthesis and complex II activity, providing a novel mechanism to promote disease aggressiveness. Citation Format: Gati Panigrahi, Prakash Praharaj, Kiran Sai, Gargi Mahapatra, Taylor Peak, Sierra Patterson, Hakeem Oufkir, Anthony Molina, Steven Kridel, Gagan Deep. Novel metabolic adaptations support proliferation of African American prostate cancer cells under hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2437.