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Many tumor cells rely on aerobic glycolysis for their continued proliferation and survival, which is in part due to actively inhibited mitochondrial function. Myc and HIF-1 are believed to promote such inhibition by upregulating gene expression of pyruvate dehydrogenase kinase 1 (PDHK1), which phosphorylates and inactivates mitochondrial pyruvate dehydrogenase complex (PDC). However, how oncogenic signals activate PDHK1 to regulate cancer cell metabolism remains unclear. we report that tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and PDC binding. Functional PDC can form in mitochondria outside of the matrix in some cancer cells and PDHK1 is commonly tyrosine phosphorylated in human cancers by diverse oncogenic tyrosine kinases localized to different mitochondrial compartments. Expression of phosphorylation-deficient, catalytic hypomorph PDHK1 mutants in cancer cells leads to decreased cell proliferation under hypoxia, increased oxidative phosphorylation with decreased lactate production and enhanced mitochondrial utilization of pyruvate, and reduced tumor growth in xenograft nude mice. Our findings suggest that tyrosine phosphorylation activates PDHK1 to inhibit mitochondrial function, providing a metabolic advantage for tumor growth. Moreover, inhibition of PDHK1 attenuates tumor growth, suggesting that PDHK1 may serve as a therapeutic target in cancer treatment.

저자

• Tae-Wook Chung [ Department of Biological Science, SungKyunKwan University, Suwon City, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA. ]
• Cheorl-Ho Kim [ Department of Biological Science, SungKyunKwan University, Suwon City, Kyunggi-Do 440-746, Korea. ]
• Jing Chen [ Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA. ]

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• 간행물명

  한국당과학회 학술대회

• 간기

  연간

• 수록기간

  2006~2022

• 십진분류

  KDC 517 DDC 614