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: 10212325
• 负责人: Amato J. Giaccia
• 金额: $ 67.29万
• 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/10212325
• 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（由申请人提供）：实体瘤（如透明细胞肾细胞癌（ccRCC））中代谢基因表达的频繁改变强化了代谢失调在驱动肿瘤扩张中的重要性。事实上，通过von Hippel Lindau（VHL）肿瘤抑制基因突变或通过暴露于缺氧，缺氧诱导型转录因子（HIF）的组成性激活导致葡萄糖摄取、糖酵解通量、乳酸分泌和线粒体活性抑制的增强。相反，由线粒体产生的活性氧刺激HIF依赖性转录，产生一个复杂的信号循环，平衡线粒体氧消耗与细胞对缺氧的反应。除了在抑制OXPHOS的同时刺激糖酵解之外，缺氧还被证明通过还原性谷氨酰胺代谢刺激从头脂肪生成，尽管还不知道这种还原性谷氨酰胺代谢如何有助于实体瘤中的脂质积累和ccRCC中的透明细胞表型。重要的是，HIF依赖的代谢变化已被用于治疗，这表明对HIF调节的代谢的更全面的理解可能会产生新的抗癌疗法。氧化代谢，广泛地包括碳水化合物氧化、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，这些转录因子一起促进线粒体的生物发生和酶功能，并且通常在包括ccRCC在内的许多肿瘤中被发现受到抑制。首先确定了它们在促进适应性产热中的作用，过氧化物酶体增殖物激活受体γ共激活物PGC-1 β和PGC-1 β通过刺激许多核转录因子的转录激活潜力在广泛的组织中促进线粒体生物合成和OXPHOS活性。PGC-1 β和PGC-1 β由离散的遗传基因座编码，并表现出不同和冗余的转录靶点。事实上，PGC-1 β-/-小鼠在氧化代谢中表现出多组织缺陷，表明PGC-1 β的独特功能不能被PGC-1 β补偿。此外，PGC-1 β缺陷型小鼠比野生型小鼠积累显著更多的体脂，并发展禁食诱导的肝脂肪变性，表明PGC-1 β在脂质代谢调节中的重要作用。虽然PGC家族的功能在正常生理学中已被广泛研究，但它们在恶性肿瘤背景下的功能尚未被严格研究。我们最近的研究表明，PGC-1 β在ccRCC中通过HIF-1 β/Dec 1转录轴被抑制。VHL-野生型肾近端小管细胞中PGC-1 β的抑制与线粒体活性降低和透明细胞（脂质和糖原积累）表型的获得（ccRCC的组织学标志）相关。这些发现提供了将透明细胞表型与肾肿瘤发生的多个方面联系起来的第一个证据，并提高了PGC-1 β刺激作为治疗肾细胞癌和潜在的其他实体瘤的新型治疗方式的潜力。这项资助的目标是探索控制癌症中脂质稳态的分子机制，表征它们对肿瘤发生的贡献，并确定它们在实体瘤中的治疗靶向方式，并确定如何在治疗上最好地利用它们。

项目成果

ACSL3 regulates lipid droplet biogenesis and ferroptosis sensitivity in clear cell renal cell carcinoma.

• DOI: 10.1186/s40170-022-00290-z
• 发表时间: 2022-10-03
• 期刊: Cancer & metabolism
• 影响因子: 5.9

Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes.

• DOI: 10.1016/j.stemcr.2021.04.018
• 发表时间: 2021-09-14
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Chang ACY;Pardon G;Chang ACH;Wu H;Ong SG;Eguchi A;Ancel S;Holbrook C;Ramunas J;Ribeiro AJS;LaGory EL;Wang H;Koleckar K;Giaccia A;Mack DL;Childers MK;Denning C;Day JW;Wu JC;Pruitt BL;Blau HM
• 通讯作者: Blau HM

Suppressing Mitochondrial Respiration Is Critical for Hypoxia Tolerance in the Fetal Growth Plate.

• DOI: 10.1016/j.devcel.2019.04.029
• 发表时间: 2019-06
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Qing Yao;M. Khan;C. Merceron;Edward L LaGory;Zachary Tata;L. Mangiavini;Jiarui Hu;Krishna G. Vemulapalli;N. Chandel;A. Giaccia;E. Schipani