{Reference Type}: Journal Article
{Title}: HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation.
{Author}: Urrutia AA;Mesa-Ciller C;Guajardo-Grence A;Alkan HF;Soro-Arnáiz I;Vandekeere A;Ferreira Campos AM;Igelmann S;Fernández-Arroyo L;Rinaldi G;Lorendeau D;De Bock K;Fendt SM;Aragonés J;
{Journal}: Cell Rep
{Volume}: 43
{Issue}: 4
{Year}: 2024 Apr 23
暂无{DOI}: 10.1016/j.celrep.2024.114103
{Abstract}: 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.