Lipid metabolism regulates cancer cell adaptation to hypoxic tumor stress

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Project summary Anabolic metabolic activity in normal mammalian cells is tightly regulated by growth factor signaling that is highly responsive to changing levels of blood-borne nutrients and oxygen (O2). In contrast, oncogene activation and tumor suppressor loss perturbs metabolic regulation to drive constitutive biosynthetic activity in cancer cells. Our recently published data indicate that this dysregulated pro- growth phenotype proves unsupportable under conditions that mimic the poorly perfused, hypoxic subdomains characteristic of solid tumors. Specifically, when cells with constitutive mTORC1 signaling were exposed to conditions of serum and O2 limitation, they exhibited highly distended ER, expressed markers of ER stress, and underwent apoptosis induced by the unfolded protein response (UPR) effectors IRE1α and TXNIP. Inhibition of either protein synthesis or mTORC1 signaling reversed these phenotypes, suggesting that elevated protein load caused ER stress and activated the UPR in these cells. Surprisingly, the addition of exogenous unsaturated fatty acids also rescued cell death, suggesting that an insufficiency of unsaturated lipids renders hypoxic, serum-deprived cancer cells incapable of expanding ER membranes to accommodate elevated protein synthesis. Importantly, a broad array of human cancer cell lines displayed a similar dependence on exogenous unsaturated lipids for survival under conditions of serum and O2 deprivation. Collectively, these data suggest a novel and general metabolic vulnerability of cancer cells that might be exploited therapeutically. The Specific Aims of this proposal are to (1) determine the molecular mechanisms whereby IRE1α and TXNIP promote cancer cell death under tumor-like stress conditions, and (2) to explore the role of lipid storage in promoting cancer cell survival. Briefly, Specific Aim 1 will investigate the mechanisms by which TXNIP expression is regulated by IRE1α, and the role of ROS in TXNIP-mediated apoptosis. Specific Aim 2 will address the cytoprotective role of lipid droplet (LD) formation in clear cell renal cell carcinoma (ccRCC) cells. Preliminary data indicate that the ADRP protein, the expression of which is regulated by Hypoxia Inducible Factor-2α, is essential for LD formation. Knocking down HIF-2α or ADRP expression activates IRE1α and induces TXNIP expression, and promotes apoptosis in ccRCC. Multiple experimental approaches will be used to dissect the causative relationship between tumor hypoxia, HIF-2α expression, ADRP function, LD formation, de novo lipogenesis and glutamine metabolism in vitro and in vivo. As elevated de novo lipogenesis and LD formation is observed in multiple cancer cell types, these results should have general implications for understanding the role of lipid transport and metabolism in malignancy.