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.

 描述（由适用提供）：诸如透明细胞肾细胞癌（CCRCC）等实体瘤中代谢基因的表达经常改变，这增强了代谢失调在驱动肿瘤扩张中失调的重要性。实际上，通过von Hippel -Lindau（VHL）抑制肿瘤抑制基因或暴露于缺氧的突变，低氧诱导转录因子（HIF）的本构激活导致葡萄糖摄取，糖酵解量增强，使线粒体活性的分泌和抑制。相反，线粒体产生的活性氧刺激了HIF依赖性转录，从而产生了复杂的信号回路，该回路平衡了线粒体氧的消耗与细胞对缺氧的反应。除了刺激糖酵解的同时抑制OXPHOS外，还证明缺氧还可以通过减少谷氨酰胺来刺激从头脂肪生成，尽管谷氨酰胺尚不知道这种减少的谷氨酰胺代谢如何导致固体瘤中的脂质积累以及CCRCC中的透明细胞表型。重要的是，已经探索了HIF依赖性的代谢变化，表明对HIF调节的代谢的更全面的了解可能会产生新型的抗癌疗法。氧化代谢广泛包含碳氧化剂氧化，谷氨酰胺氧化和脂肪酸β-氧化，由许多核和线粒体转录因子控制，共同促进了线粒体的生物发生和酶促作用，并经常在包括CCRCC在内的许多Tumors中被发现。首先确定其在促进自适应热生成中的作用，过氧化物组增殖剂激活受体γ共激活剂PGC-1和PGC-1ß通过刺激核转录因子数量的转录激活潜力，在各种组织中促进线粒体生物发生和Oxphos活性。 PGC-1和PGC-1ß由离散的遗传局部和展示不同的和冗余的转录靶标编码。实际上，PGC-1 - / - 小鼠在氧化代谢中表现出多组织缺陷，表明PGC-1无法补偿PGC-1ß的独特功能。此外，PGC-1缺乏小鼠积累的体内脂肪明显高于野生型小鼠，并且发展为禁食诱导的肝脂肪变性，这表明PGC-1在调节脂质代谢中起着重要作用。尽管PGC家族的功能已广泛研究了正常生理学，但在恶性肿瘤的背景下，它们的功能尚未经过严格研究。我们最近的研究表明，PGC-1通过HIF-/DEC1转录轴抑制了CCRCC。 PGC-1在VHL野生型肾脏近端细胞细胞中的抑制与线粒体活性的降低以及透明细胞（脂质和糖原积累）表型相关，这是CCRCC的组织学标志。这些发现提供了第一个证据，将透明细胞表型与肾脏肿瘤发生的多个方面联系起来，并提高了PGC-1刺激的潜力，作为治疗肾细胞癌和潜在的其他实体瘤的新型热方式。该赠款的目标是探索癌症中脂质稳态的分子机制，表征它们对肿瘤发生的贡献，并确定它们可以在实体瘤中热靶向的方法，并确定如何最好地通过治疗探索它们。