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）使葡萄糖的代谢从高效的氧化磷酸化转变为效率较低的糖酵解。如此积累的丙酮酸被氧化成乳酸，然后将其泵送到肿瘤微环境中。从戊糖磷酸途径（PPP）产生的质子以及在ATP水解后产生的质子进一步增强了肿瘤微环境中的酸度。肿瘤微环境中产生的pH值会激活内质网蛋白：固醇调节元件结合蛋白1c（SREBP-1c），该蛋白一旦被激活，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，在氧气存在下会导致HIF-1α降解。PHD2的化学活化可以下调HIF-1α，从而恢复其所有作用。