Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism

• Authors: Taro Hitosugi, Emory University; Jun Fan, Emory University; Tae-Wook Chung, Emory University; Katherine Lythgoe, Emory University; Xu Wang, Emory University; Jianxin Xie, Cell Signaling Technology, Inc.; Qingyuan Ge, Cell Signaling Technology, Inc.; Ting-Lei Gu, Cell Signaling Technology, Inc.; Roberto D. Polakiewicz, Cell Signaling Technology, Inc.; Johannes L. Roesel, Novartis Pharma AG; Georgia Chen, Emory University; Titus J. Boggon, Yale University; Sagar Lonial, Emory University; Haian Fu, Emory University; Fadlo Khuri, Emory University; Sumin Kang, Emory University; Jing Chen, Emory University
• Journal Title: Molecular Cell
• Volume: Volume 44, Number 6
• Publisher: Elsevier (Cell Press) | 2011-12-23, Pages 864-877
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.molcel.2011.10.015
• Subjects: Health Sciences, Oncology

Abstract

Many tumor cells rely on aerobic glycolysis instead of oxidative phosphorylation for their continued proliferation and survival. Myc and HIF-1 are believed to promote such a metabolic switch by, in part, upregulating gene expression of pyruvate dehydrogenase (PDH) kinase 1 (PDHK1), which phosphorylates and inactivates mitochondrial PDH and consequently pyruvate dehydrogenase complex (PDC). Here we report that tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and PDC binding. Functional PDC can form in mitochondria outside of 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 and increased oxidative phosphorylation with enhanced mitochondrial utilization of pyruvate, and reduced tumor growth in xenograft nude mice. Together, tyrosine phosphorylation activates PDHK1 to promote the Warburg effect and tumor growth.