%0 Journal Article
%T HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation.
%A Urrutia AA
%A Mesa-Ciller C
%A Guajardo-Grence A
%A Alkan HF
%A Soro-Arnáiz I
%A Vandekeere A
%A Ferreira Campos AM
%A Igelmann S
%A Fernández-Arroyo L
%A Rinaldi G
%A Lorendeau D
%A De Bock K
%A Fendt SM
%A Aragonés J
%J Cell Rep
%V 43
%N 4
%D 2024 Apr 23
%M 38607920
暂无%R 10.1016/j.celrep.2024.114103
%X Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find 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 the 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.