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

 描述（由申请人提供）：实体瘤（例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) 肿瘤抑制基因的突变或通过暴露于缺氧，缺氧诱导转录因子 (HIF) 的组成型激活会导致葡萄糖摄取、糖酵解通量、乳酸分泌增强和线粒体活性抑制。相反，线粒体产生的活性氧会刺激 HIF 依赖性转录，从而创建一个复杂的信号回路，平衡线粒体耗氧量与细胞对缺氧的反应。除了刺激糖酵解同时抑制 OXPHOS 之外，缺氧还被证明可以通过还原性谷氨酰胺代谢刺激从头脂肪生成，尽管目前尚不清楚这种还原性谷氨酰胺代谢如何促进实体瘤中的脂质积累和 ccRCC 中的透明细胞表型。重要的是，HIF 依赖性代谢变化已在治疗上得到利用，这表明对 HIF 调节代谢的更全面了解可能会产生新的抗癌疗法。氧化代谢广泛包括碳水化合物氧化、谷氨酰胺氧化和脂肪酸β-氧化，由许多核转录因子和线粒体转录因子控制，这些转录因子共同促进线粒体的生物发生和酶功能，并且在包括 ccRCC 在内的许多肿瘤中经常被发现受到抑制。过氧化物酶体增殖物激活受体 γ 共激活剂 PGC-1 和 PGC-1ß 首次被发现在促进适应性产热方面发挥作用，通过刺激许多核转录因子的转录激活潜力，促进多种组织中的线粒体生物发生和 OXPHOS 活性。 PGC-1 和 PGC-1ß 由离散的基因位点编码，并表现出不同和冗余的转录目标。事实上，PGC-1α -/- 小鼠在氧化代谢中表现出多组织缺陷，表明 PGC-1α 具有无法通过 PGC-1ß 补偿的独特功能。此外，PGC-1α缺陷小鼠比野生型小鼠积累明显更多的体脂肪，并出现禁食诱导的肝脂肪变性，这表明PGC-1α在脂质代谢调节中发挥重要作用。虽然 PGC 家族的功能在正常生理学中已得到广泛研究，但其在恶性肿瘤中的功能尚未得到严格研究。我们最近的研究表明，PGC-1α 在 ccRCC 中通过 HIF-α/Dec1 转录轴受到抑制。 VHL 野生型肾近曲小管细胞中 PGC-1α 的抑制与线粒体活性降低和透明细胞（脂质和糖原积累）表型的获得有关，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肿瘤发​​生的多个方面联系起来，并提高了 PGC-1α 刺激作为治疗肾细胞癌和其他潜在实体瘤的新型治疗方式的潜力。该资助的目标是探索控制癌症中脂质稳态的分子机制，描述它们对肿瘤发生的贡献，确定它们在实体瘤中的治疗靶点，并确定如何最好地利用它们进行治疗。

 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.