Abstract 4316: BNIP3 suppresses mammary tumorigenesis and metastasis through negative regulation of Warburg effect and HIF-1α
Authors: Aparajita Hoskote Chourasia, Kristin Tracy, Michelle Boland, Marina Sharifi, Kay F. Macleod
Journal: Cancer Research (2014)

Abstract BNIP3 is a hypoxia-inducible protein involved in mitochondrial dynamics and mitophagy that is up-regulated at pre-malignant stages of various human cancers, including breast cancer but down-regulated at later stages of tumorigenesis. To examine the role of BNip3 in tumor progression, we crossed BNip3 null mice to the MMTV-PyMT mouse model of breast cancer. Loss of BNip3 promoted primary tumor growth in vivo and tumor cell proliferation in vitro and was associated with increased aerobic glycolysis and reduced mitochondrial respiration. BNip3 null tumor cells also showed increased invasive properties that were cell intrinsic and transplantable to wild-type host mice. Consistently, there was reduced latency to lung metastasis in the MMTV-PyMT;BNip3-/- mice and increased numbers of metastases compared to control mice. BNip3 null tumors exhibited increased mitochondrial mass, but a greater fraction of mitochondria were dysfunctional with reduced membrane potential and decreased metabolite uptake compared to BNip3 wild-type tumor cells. Consistently, increased proliferation of BNip3 null tumor cells was associated with increased carbon flux from glucose to lipid and nucleic acids. Interestingly, although mitochondria were less efficient at uptake of pyruvate and glutamine, the rate of production of Krebs cycle intermediates was increased. This indicates that defective mitochondria due to inefficient mitophagy can induce the Warburg effect, as originally proposed by Warburg himself. Loss of BNip3 also resulted in more hypoxic tumors that expressed increased levels of Hif-1α and its target genes and showed increased angiogenesis, although blood vessels were abnormal possibly explaining increased tumor hypoxia, thus suggesting a negative feedback loop between Hif-1α and its target gene, BNip3. Inhibition of glycolysis or inhibition of HIF activity reduced proliferation in BNip3 null tumor cells to the levels observed in control cells. Significantly, BNip3 null tumor cells underwent autophagic flux as efficiently as wild-type cells demonstrating for the first time that inhibition of mitophagy has a distinct tumorigenic consequence to general inactivation of autophagy, as reported elsewhere. These results demonstrate that BNip3 has tumor and metastasis suppressor properties required to maintain mitochondrial integrity, promote oxidative metabolism and mitigate against the metastasis promoting activities of hypoxia and glycolytic metabolism. Citation Format: Aparajita Hoskote Chourasia, Kristin Tracy, Michelle Boland, Marina Sharifi, Kay F. Macleod. BNIP3 suppresses mammary tumorigenesis and metastasis through negative regulation of Warburg effect and HIF-1α. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4316. doi:10.1158/1538-7445.AM2014-4316