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Solving a paradox of hypoxic metabolism reveals driver of cancer cell proliferation

Chi Van Dang, Ludwig Cancer Research
Chi Van Dang

A study co-led by Ludwig Institute Scientific Director Chi Van Dang used a reporter of HIF-1α activity in hypoxic cancer cells to track the temporal dynamics of the oxygen sensing protein in individual cells and explore a paradox of its effects on cancer cell metabolism. When oxygen is in low supply, HIF-1α —which controls a complex program of gene expression—can drive glycolysis, in which energy is extracted from sugar in a manner that produces an acid named lactate. Glycolysis and the normal processes of energy extraction from sugar—mitochondrial respiration—tend to be mutually exclusive. Yet HIF-1α seems able to activate both processes in cancer cells, an inconsistency in its effects that was not quite understood. Chi and his colleagues reported in a Cell Systems paper in December that HIF-1α-driven gene expression oscillates in a small subpopulation of hypoxic cancer cells. The oscillations, they show, are driven by lactate and associated in these few cells with the intermittent use of mitochondrial respiration; most hypoxic cells, however, continue to rely on glycolysis. They also show that lactate can serve as a nutrient and messenger to convey information about cell density in hypoxic subregions of the tumor. The oscillatory HIF-1α activity in the few cells pushes them out of the cell cycle arrest induced by hypoxia, inhibits the expression of tumor suppressor genes and promotes the expression of oncogenes that drive cancer cell proliferation.

Lactate-dependent chaperone-mediated autophagy induces oscillatory HIF-1α activity promoting proliferation of hypoxic cells
Cell Systems, 2022 December 2

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