Department of Pharmaceutical Sciences, School of Biosciences and Biotechnology, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India.
Department of Pharmaceutical Sciences, King Faisal University, Al-Ahsa, Saudi Arabia.
Drug Discov Today. 2018 Nov;23(11):1873-1882. doi: 10.1016/j.drudis.2018.05.016. Epub 2018 May 14.
Hypoxia-inducible factor-1α (HIF-1α) shifts the metabolism of glucose from highly efficient oxidative phosphorylation to less efficient glycolysis. Pyruvic acid thus accumulated is oxidized to lactic acid which is pumped out in the tumor microenvironment. Protons generated from the pentose phosphate pathway (PPP) and upon hydrolysis of ATP further enhance the acidity in the tumor microenvironment. The resultant pH in the tumor microenvironment activates an endoplasmic reticulum protein: sterol regulatory element binding protein-1c (SREBP-1c), which once activated enhances proliferation of the tumor cell. Prolyl hydroxylase 2 (PHD2) is a negative regulator of HIF-1α and causes degradation of HIF-1α in the presence of oxygen. Chemical activation of PHD2 can downregulate HIF-1α and thus restore all its effects. The present review is an attempt to describe PHD2 as the target to combat cancer hypoxia and consequential cellular and metabolic alterations.
缺氧诱导因子-1α（HIF-1α）将葡萄糖代谢从高效的氧化磷酸化转变为效率较低的糖酵解。因此，积累的丙酮酸被氧化为乳酸，乳酸在肿瘤微环境中被泵出。戊糖磷酸途径（PPP）产生的质子和 ATP 水解进一步增强了肿瘤微环境的酸度。肿瘤微环境中的最终 pH 值激活内质网蛋白：固醇调节元件结合蛋白-1c（SREBP-1c），一旦被激活，就会增强肿瘤细胞的增殖。脯氨酰羟化酶 2（PHD2）是 HIF-1α 的负调节剂，在氧气存在的情况下导致 HIF-1α的降解。PHD2 的化学激活可以下调 HIF-1α，从而恢复其所有作用。本综述试图将 PHD2 描述为对抗癌症缺氧以及随之而来的细胞和代谢改变的靶点。
