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• W3210474281 abstract "4109 The hypoxia-inducible transcription factors, HIF-1 and HIF-2, have been strongly associated with cancer cell growth and survival. HIF-1 is composed of the HIF-1α and HIF-1β subunits; and HIF-2 is composed of the HIF-2α and HIF-1β subunits. Whereas HIF-1β is constitutively expressed, HIF-1α and HIF-2α protein stability and synthesis are regulated by intratumoral hypoxia and genetic alterations in oncogenes and tumor suppressor genes. Cancer cells balance glycolysis and aerobic respiration in metabolizing glucose. The role of HIF-1α in mediating glycolysis is well-described. Recently, HIF-1α has been implicated in regulating mitochondrial respiration. The role of HIF-2α in glucose metabolism remains unclear. We hypothesized that HIF-1α and HIF-2α (HIF-αs) cooperate to promote cancer glucose metabolism. To examine the roles of HIF-αs, we disrupted the HIF-1α and HIF-2α genes, alone and in combination, in two human colon cancer cell lines: HCT116 and RKO. Expression of both HIF-αs led to a 5-fold increase in in vitro and in vivo tumor growth. Consistent with the literature, HIF-1α, but not HIF-2α, mediated aerobic glycolysis, as measured by cellular ATP and lactate levels. In addition, both HIF-αs were required to promote mitochondrial respiration efficiency. Specifically, loss of both HIF-αs led to a 3-fold increase in mitochondrial and cellular ROS (as measured by MitoSOX Red and DCFDA), a 2-fold increase in mitochondrial hyperpolarization (as measured by the ratio of MitoTracker Red CMXRos to MitoTracker Green FM), and a 4-fold decrease in oxygen consumption (as measured by the oxygen-sensing fluorescent dye (Ru(DPP)3)). We next determined the mechanisms by which HIF-αs promote mitochondrial respiration efficiency. Cardiolipin is a mitochondrial phospholipid that interacts with electron transport chain proteins to optimize mitochondrial respiration. Global lipidome analyses on isolated mitochondria revealed that the presence of both HIF-αs induced the synthesis of mitochondrial cardiolipin species by 3-6-fold. Microarray analyses identified a novel set of HIF-αs target genes. Two of these genes were PCK2 and ACSL5, which encode for mitochondrial enzymes that catalyze essential steps in cardiolipin synthesis. Subsequent analyses in multiple cell lines confirmed that HIF-αs induce mitochondrial PCK2 and ACSL5 expression by ~4-fold. In addition, mitochondrial PCK2 and ACSL5 expression were ~3-fold increased in human colorectal cancer cancers compared to their adjacent normal mucosa. Together, these data elucidate a novel growth-promoting bioenergetic pathway, in which both HIF-αs induce the expression of genes important for mitochondrial cardiolipin synthesis (PCK2 and ACSL5). This results in increased levels of cardiolipin, an important component of the inner mitochondrial membrane. The consequent increase in mitochondrial respiration efficiency contributes to tumor growth." @default.
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• W3210474281 date "2008-05-01" @default.
• W3210474281 modified "2023-10-18" @default.
• W3210474281 title "HIF-αs promote mitochondrial cardiolipin synthesis and respiration efficiency" @default.
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