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

 描述(申请人提供)：代谢基因在实体肿瘤，如透明细胞肾细胞癌(CcRCC)中的表达频繁变化，加强了代谢失调在推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暴露在低氧环境中，低氧诱导转录因子(HIF)的结构性激活，导致葡萄糖摄取、糖酵解通量、乳酸分泌增加和线粒体活性抑制。相反，线粒体产生的活性氧物种刺激依赖于HIF的转录，创建一个复杂的信号循环，平衡线粒体的氧气消耗和细胞对低氧的反应。除了在抑制OXPHOS的同时刺激糖酵解，低氧也被证明通过还原型谷氨酰胺代谢刺激新生脂肪生成，尽管目前还不知道这种还原型谷氨酰胺代谢如何促进实体瘤中的脂肪积累和ccRCC中的透明细胞表型。重要的是，HIF依赖的代谢变化已经被用于治疗，这表明更全面地了解HIF调节的代谢可能会产生新的抗癌疗法。氧化代谢包括碳水化合物氧化、谷氨酰胺氧化和脂肪酸氧化，受多种核和线粒体转录因子的控制，这些转录因子共同促进线粒体的生物发生和酶功能，在许多肿瘤中经常被发现抑制，包括肾细胞癌。过氧化体增殖物激活受体共激活剂pgc-1和pgc-1？通过刺激许多核转录因子的转录激活潜能，在广泛的组织中促进线粒体的生物发生和氧合酶的活性，首次被确定为促进适应性产热的作用。PGC-1和pGC-1？由离散的遗传位点编码，既有不同的转录靶点，也有多余的转录靶点。事实上，pGC-1-/-小鼠在氧化代谢方面表现出多个组织缺陷，表明pGC-1的独特功能不能被pgc-1？弥补。此外，pGC-1缺陷小鼠比野生型小鼠积累更多的体脂，并出现空腹引起的肝脏脂肪变性，提示pGC-1在脂代谢调节中起重要作用。虽然PGC家族在正常生理学中的功能已经被广泛研究，但它们在恶性肿瘤背景下的功能还没有得到严格的研究。我们最近的研究表明，PGC-1在肾细胞癌中是通过HIF-/DEC1转录轴被抑制的。野生型肾小管上皮细胞PGC-1的抑制与线粒体活性降低和获得透明细胞(脂质和糖原积聚)表型有关，而透明细胞是肾细胞癌的组织学标志。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刺激作为治疗肾癌以及潜在的其他实体肿瘤的一种新的治疗方式的潜力。这笔赠款的目标是探索控制癌症中脂质动态平衡的分子机制，确定它们在肿瘤发生中的作用，确定它们可以作为实体肿瘤的治疗靶点的方法，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.