Abstract A21: ACC1 is required for prostate cancer initiation, but not progression?

The majority of cancers undergo metabolic alterations during initiation and progression of disease. Increased de novo lipogenesis is recognized as metabolic mark of cancer cells. The enzymes responsible for de novo fatty acid synthesis are often overexpressed in cancer, indicating that these enzymes are potential and promising targets for novel therapies. Acetyl CoA Carboxylase 1 (ACC1) is a cytosolic enzyme which catalyzes the rate limiting step of de novo fatty acid synthesis through the ATP and biotin-dependent carboxylation of acetyl-CoA to malonyl-CoA. In doing so, it regulates both fatty acid and acetate metabolism. Both pharmacological inhibition and siRNA knockdown of ACC1 have been demonstrated to deny prostate cancer cells of necessary amounts of fatty acids needs to proliferate, resulting in selective toxicity. Although previous research indicates ACC1 and the entire process of fatty acid metabolism to be promising avenues for novel therapy development, much remains to be understood. To address this, we have generated mice with prostate-specific deletion of exon 22 of the Acetyl CoA Carboxylase 1 (ACCL/L) gene by breeding with Probasin-Cre mice. Loss of ACC1 activity does not affect prostate development as survival, prostate weight, histology, and breeding were similar between ACCL/L; Cre+ and ACCL/L Cre- mice. By breeding ACC+/L mice with the established Pten knockout model of prostate cancer (PtenL/L; Cre+), we have found that homozygous inactivation of ACC1 (ACCL/L; PtenL/L; Cre+) is able to reduce tumor burden in mice at 12 weeks of age when compared to ACC+/+; PtenL/L; Cre+ littermates (average total prostate weight of 90mg versus 120mg respectively, normalized to body weight, p 0.05). In our efforts to detail why ACC1 inactivation dampens early tumor burden but not later cancer progression, we have found that tumors from both 12 and 24 week old ACCL/L; PtenL/L; Cre+ mice show no changes in lipid profile when compared to tumors arising from age-matched ACC+/+; PtenL/L; Cre+ siblings. Interestingly, through metabolic analysis, we have found that different prostate cancer cell lines utilize fatty acids in unique ways. Under conditions that mimic bioenergetic stress, only androgen insensitive DU145 cells, and not LNCaPs, were able to oxidize exogenous fatty acids. Moreover, treatment with the non-isoform specific ACC inhibitor TOFA (5-Tetradecyloxy-2-furoic acid) abolished fatty acid oxidation under such conditions. These data indicate a potential for metabolic rewiring associated with disease progression and/or metabolic stress, and that blockade of ACC1 may not be sufficient to prevent disease progression. The role of ACC1 in acetate metabolism, redox modulation, fatty acid oxidation, and compensation for ACC1 activity by ACC2 are all potential mechanisms by which ACC1-deficient prostate cancer cells are able to survive and proliferate. Ultimately, these data further the notion that tumors rewire their metabolic circuits to meet the demands associated with cancer biology. Citation Format: Amanda L. Davis, Kristen Scott, Wu Jiansheng, Yong Q. Chen, Steven J. Kridel. ACC1 is required for prostate cancer initiation, but not progression? [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A21.