The Impact of Mitochondrial Repression and Lipid Accumulation by HIF on Tumor Growth

HIF 抑制线粒体和脂质积累对肿瘤生长的影响

• 批准号: 9976465
• 负责人: Amato J. Giaccia
• 金额: $ 76.29万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976465
• 关键词: Automobile Driving; Biogenesis; Body fat; Carbohydrates; Cell Hypoxia; Cell Respiration; Cells; Clear Cell; Defect; Equilibrium; Exhibits; Exposure to; Family; Fasting; Fatty Acids; Fatty Liver; Genes; Genetic Transcription; Glutamine; Glycogen; Glycolysis; Goals; Grant; Histologic; Homeostasis; Hypoxia; Intracellular Accumulation of Lipids; Kidney; Link; Lipids; Malignant Neoplasms; Metabolic; Metabolism; Mitochondria; Modality; Molecular; Mus; Mutation; Nuclear; Oxygen Consumption; PPAR gamma; Phenotype; Physiology; Production; Proximal Kidney Tubules; Reactive Oxygen Species; Regulation; Renal Cell Carcinoma; Repression; Role; Signal Transduction; Solid Neoplasm; Source; Therapeutic; Thermogenesis; Tissues; Transcriptional Activation; Tumor Expansion; Tumor Suppressor Genes; Wild Type Mouse; cancer therapy; genomic locus; glucose uptake; lipid biosynthesis; lipid metabolism; novel; novel therapeutics; oxidation; public health relevance; respiratory; response; therapeutic target; transcription factor; tumor; tumor growth; tumorigenesis

 DESCRIPTION (provided by applicant): The frequently altered expression of metabolism genes in solid tumors such as clear cell renal cell cancer (ccRCC) has reinforced the importance of dysregulated metabolism in driving tumor expansion. Indeed, constitutive activation of the hypoxia inducible transcription factor (HIF) through mutations in the von Hippel Lindau (VHL) tumor suppressor gene or through exposure to hypoxia, results in enhanced glucose uptake, glycolytic flux, lactate secretion and suppression of mitochondrial activity. Conversely, reactive oxygen species produced by the mitochondria stimulate HIF-dependent transcription, creating an intricate signaling loop that balances mitochondrial oxygen consumption with the cellular response to hypoxia. In addition to stimulating glycolysis while suppressing OXPHOS, hypoxia has also been demonstrated to stimulate de novo lipogenesis through reductive glutamine metabolism, although it has not yet known how this reductive glutamine metabolism contributes to lipid accumulation in solid tumors and the clear cell phenotype in ccRCC. Importantly, HIF-dependent metabolic changes have been exploited therapeutically, indicating that a more comprehensive understanding of HIF regulated metabolism may yield novel anti-cancer therapies. Oxidative metabolism, which broadly encompasses carbohydrate oxidation, glutamine oxidation, and fatty acid ß-oxidation, is controlled by a number of nuclear and mitochondrial transcription factors that together promote the biogenesis and enzymatic function of mitochondria and is often found repressed in many tumors including ccRCC. First identified for their role in promoting adaptive thermogenesis, the peroxisome proliferator activated receptor gamma coactivators PGC-1 and PGC-1ß promote mitochondrial biogenesis and OXPHOS activity in a wide range of tissues by stimulating the transcriptional activation potential of a number of nuclear transcription factors. PGC-1 and PGC-1ß are encoded by discrete genetic loci and exhibit both distinct and redundant transcriptional targets. Indeed, PGC-1 -/- mice exhibit multi-tissue defects in oxidative metabolism, indicating unique functions for PGC-1 that cannot be compensated for by PGC-1ß. Furthermore, PGC-1 deficient mice accumulate significantly more body fat than wild type mice, and develop fasting induced hepatic steatosis, suggesting an important role for PGC-1 in the regulation of lipid metabolism. While the functions of the PGC family have been extensively studied in normal physiology, their function in the context of malignancy has not been rigorously investigated. Our recent studies indicate that PGC-1 is suppressed in ccRCC through a HIF-/Dec1 transcriptional axis. The suppression of PGC-1 in VHL-wild type renal proximal tubule cells is associated with reduced mitochondrial activity and acquisition of the clear cell (lipid and glycogen accumulation) phenotype, a histological hallmark of ccRCC. These findings provide the first evidence linking the clear cell phenotype to multiple aspects of renal tumorigenesis and raise the potential for PGC-1 stimulation as a novel therapeutic modality in the treatment of renal cell carcinoma, and potentially other solid tumors. The goals of this grant are to explore the molecular mechanisms governing lipid homeostasis in cancer, characterize their contribution to tumorigenesis and identify ways that they can be therapeutically targeted in solid tumors and determine how to best exploit them therapeutically.