Pyruvate dehydrogenase PDH-E1{beta} controls tumor progression by altering the metabolic status of cancer cells.

Downregulation of pyruvate dehydrogenase (PDH) is critical for the aberrant preferential activation of glycolysis in cancer cells under normoxic conditions. Phosphorylation-dependent inhibition of PDH is a relevant event in this process, but it is not durable since it relies on PDH kinases which are activated ordinarily under hypoxic conditions. Thus, it remains unclear how PDH is durably downregulated in cancer cells that are not hypoxic. Building on evidence that PDH activity depends on the stability of a multi-protein PDH complex, we found that the PDH-E1β subunit of the PDH complex is downregulated to inhibit PDH activity under conditions of prolonged hypoxia. After restoration of normoxic conditions, reduced expression of PDH-E1β was sustained such that glycolysis remained highly activated. Notably, PDH-E1β silencing in cancer cells produced a metabolic state strongly resembling the Warburg effect, but inhibited tumor growth. Conversely, enforced exogenous expression of PDH-E1β durably increased PDH activity and promoted the malignant growth of breast cancer cells in vivo. Taken together, our results establish the specific mechanism through which PDH acts as an oncogenic factor by tuning glycolytic metabolism in cancer cells.

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