BNip3 is a mitochondrial protein that promotes the turnover of mitochondria at the autophagolysosome when nutrient supplies are low. BNip3-null livers exhibit lipid accumulation and develop a phenotype mimicking non-alcoholic steatohepatitis, a known precursor for development of hepatocellular carcinoma (HCC). Additionally, BNip3 is silenced in human HCC and other malignancies and this loss often correlates with more aggressive tumors and worse outcomes. However, the functional significance of BNIP3 loss for growth and progression of HCC has not been determined. We utilized the diethylnitrosamine (DEN)-induced mouse model of HCC to determine how loss of BNip3 affected HCC development in the mouse. Wild type and BNip3-null mice were treated with DEN, and tumor burden (size and number) was assessed at 6, 8, and 10 months of age. We also generated primary HCC cell lines from the tumors arising in BNip3-null mice for in vitro analysis of tumor cell growth and metabolism. We observed that BNip3-null mice had reduced tumor latency and enhanced tumor growth rate in the liver following DEN treatment compared to wild type mice consistent with BNip3 functioning as a tumor suppressor of HCC. Interestingly, tumors arising in BNip3-null mice accumulated increased lipid and qPCR analysis of primary tumors and cell lines revealed increased expression of lipogenesis genes compared to wild type. Treatment with a novel fatty acid synthase inhibitor or re-expression of BNip3 in the BNip3-null HCC cell lines reduced tumor cell growth and lipogenesis, and promoted oxidative metabolism. These results indicate that BNip3 acts as a tumor suppressor in HCC by limiting de novo lipogenesis and suggest that fatty acid synthase inhibitors could be effective therapeutically against BNIP3 deficient HCC in patients.
Citation Format: Kay F. Macleod. BNip3 suppresses hepatocellular carcinoma (HCC) growth by limiting lipogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4984. doi:10.1158/1538-7445.AM2017-4984