The interplay between MYC and HIF in the Warburg effect.

C V Dang
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引用次数: 111

Abstract

c-MYC and the hypoxia-inducible factors (HIFs) are critical factors for tumorigenesis in a large number of human cancers. While the normal function of MYC involves the induction of cell proliferation and enhancement of cellular metabolism, the function of HIF, particularly HIF-1, involves adaptation to the hypoxic microenvironment, including activation of anaerobic glycolysis. When MYC-dependent tumors grow, the hypoxic tumor microenvironment elevates the levels of HIF, such that oncogenic MYC and HIF collaborate to enhance the cancer cell's metabolic needs through increased uptake of glucose and its conversion to lactate. HIF is also able to attenuate mitochondrial respiration through the induction of pyruvate dehydrogenase kinase 1 (PDK1), which in part accounts for the Warburg effect that describes the propensity for cancers to avidly take up glucose and convert it to lactate with the concurrent decrease in mitochondrial respiration. Target genes that are common to both HIF and MYC, such as PDK1, LDHA, HK2, and TFRC, are therefore attractive therapeutic targets, because their coordinate induction by HIF and MYC widens the therapeutic window between cancer and normal tissues.

Warburg效应中MYC和HIF的相互作用。
c-MYC和缺氧诱导因子(hif)是许多人类癌症发生的关键因素。MYC的正常功能包括诱导细胞增殖和增强细胞代谢,而HIF,特别是HIF-1的功能包括对缺氧微环境的适应,包括厌氧糖酵解的激活。当MYC依赖性肿瘤生长时,低氧肿瘤微环境会提高HIF水平,从而致癌MYC和HIF通过增加葡萄糖的摄取并将其转化为乳酸来增强癌细胞的代谢需求。HIF还能够通过诱导丙酮酸脱氢酶激酶1 (PDK1)来减弱线粒体呼吸,这在一定程度上解释了Warburg效应,该效应描述了癌症在线粒体呼吸减少的同时大量摄取葡萄糖并将其转化为乳酸的倾向。因此,HIF和MYC共有的靶基因,如PDK1、LDHA、HK2和TFRC,是有吸引力的治疗靶点,因为它们由HIF和MYC协同诱导,扩大了癌症和正常组织之间的治疗窗口。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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