NAD+ metabolism controls growth inhibition by HIF1 in normoxia and determines differential sensitivity of normal and cancer cells.
NAD+ metabolism controls growth inhibition by HIF1 in normoxia and determines differential sensitivity of normal and cancer cells.
复制标题
NAD 代谢控制常氧条件下 HIF1 的生长抑制，并决定正常细胞和癌细胞的不同敏感性。
DOI：
10.1080/15384101.2021.1959988
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Zhitkovich,Anatoly
中科院分区：
文献类型：
--
作者：
Luczak,MichalW;Krawic,Casey;Zhitkovich,Anatoly
缺氧诱导的转录因子 HIF1 通过鲜为人知的机制抑制常氧条件下的细胞生长。缺氧反应的组成性上调与恶性肿瘤的增加有关，表明癌细胞中 HIF1 的抗增殖作用丧失。为了了解这些差异，我们检查了常氧条件下激活缺氧反应的原代人类细胞的细胞周期控制。激活的 HIF1 导致 G1、S 和 G2 期细胞周期进程整体减慢，导致有丝分裂细胞丧失。细胞周期抑制需要延长 HIF1 激活，并且与 p53 或 CDK 抑制剂 p16、p21 或 p27 的上调无关。 HIF1 的生长抑制与其 Asn803 羟基化或 HIF2 的存在无关。抑制乳酸脱氢酶可以减轻缺氧反应的抗增殖作用，更有效的是，可以通过促进细胞产生 NAD+ 来减轻这种作用，而 NAD+ 的产生会因 HIF1 激活而减少。与正常细胞相比，各种癌细胞系的 NAMPT 表达高出数倍，NAMPT 是 NAD+ 主要生物合成途径中的限速酶。抑制过表达癌细胞中的 NAMPT 活性使它们对 HIF1 的抗生长作用敏感。因此，癌细胞中的代谢变化（例如 NAD+ 产生增强）会产生对 HIF1 生长抑制活性的抵抗力，从而使其发挥促肿瘤特性。缩写：DMOG：二甲基草酰甘氨酸，DM-NOFD：二甲基 N-草酰基-D-苯丙氨酸，NMN：β-烟酰胺单核苷酸
The hypoxia-induced transcription factor HIF1 inhibits cell growth in normoxia through poorly understood mechanisms. A constitutive upregulation of hypoxia response is associated with increased malignancy, indicating a loss of antiproliferative effects of HIF1 in cancer cells. To understand these differences, we examined the control of cell cycle in primary human cells with activated hypoxia response in normoxia. Activated HIF1 caused a global slowdown of cell cycle progression through G1, S and G2 phases leading to the loss of mitotic cells. Cell cycle inhibition required a prolonged HIF1 activation and was not associated with upregulation of p53 or the CDK inhibitors p16, p21 or p27. Growth inhibition by HIF1 was independent of its Asn803 hydroxylation or the presence of HIF2. Antiproliferative effects of hypoxia response were alleviated by inhibition of lactate dehydrogenase and, more effectively, by boosting cellular production of NAD+, which was decreased by HIF1 activation. In comparison to normal cells, various cancer lines showed several fold-higher expressions of NAMPT, which is a rate-limiting enzyme in the main biosynthetic pathway for NAD+. Inhibition of NAMPT activity in overexpressor cancer cells sensitized them to antigrowth effects of HIF1. Thus, metabolic changes in cancer cells, such as enhanced NAD+production, create resistance to growth-inhibitory activity of HIF1 permitting manifestation of its tumor-promoting properties.Abbreviations: DMOG: dimethyloxalylglycine, DM-NOFD: dimethyl N-oxalyl-D-phenylalanine, NMN: β-nicotinamide mononucleotide