Hif1α-Dependent Uncoupling Of Glycolysis Suppresses Tumor Cell Proliferation

Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. Paradoxically, it remains unknown why lower glycolysis is compromised in human clear cell renal cell carcinomas (ccRCC), in which HIF1α acts a tumor suppressor by inhibiting cell autonomous proliferation. Here we found that unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio.