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7069556 
Journal Article 
Pyruvate Dehydrogenase PDH-E1 beta Controls Tumor Progression by Altering the Metabolic Status of Cancer Cells 
Yonashiro, Ryo; Eguchi, K; Wake, M; Takeda, N; Nakayama, Koh; , 
2018 
Yes 
Cancer Research
ISSN: 0008-5472
EISSN: 1538-7445 
AMER ASSOC CANCER RESEARCH 
PHILADELPHIA 
1592-1603 
29436427 
WOS:000429008900002 
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 as it relies on PDH kinases that 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-E1 beta 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-E1 beta was sustained such that glycolysis remained highly activated. Notably, PDH-E1 beta silencing in cancer cells produced a metabolic state strongly resembling the Warburg effect, but inhibited tumor growth. Conversely, enforced exogenous expression of PDH-E1 beta 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.Significance: This seminal study offers a mechanistic explanation for why glycolysis is aberrantly activated in normoxic cancer cells, offering insights into this long-standing hallmark of cancer termed the Warburg effect. (C) 2018 AACR.