Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters
Oncogene.2015 Oct 5. doi: 10.1038/onc.2015.360. [Epub ahead of print]
MetabolictargetingofoncogeneMYCbyselectiveactivationof theproton-coupledmonocarboxylatefamilyoftransporters.
Gan L
1,
2,
Xiu R
2,
Ren P
2,
Yue M
2,
Su H
3,
Guo G
3,
Xiao D
2,
Yu J
4,
Jiang H
4,
Liu H
3,
Hu G
1,
Qing G
2,
5.
- 1Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
- 2School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
- 3School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
- 4Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
- 5Medical Research Institute, Wuhan University, Wuhan, People's Republic of China.
Abstract
Deregulation of theMYConcogeneproducesMycprotein that regulates multiple aspects of cancer cell metabolism, contributing to the acquisition of building blocks essential for cancer cell growth and proliferation. Therefore, disablingMycfunction represents an attractive therapeutic option for cancer treatment. However, pharmacological strategies capable of directlytargetingMycremain elusive. Here, we identified that 3-bromopyruvate (3-BrPA), a drug candidate that primarily inhibits glycolysis, preferentially induced massive cell death in human cancer cells overexpressing theMYConcogene, in vitro and in vivo, without appreciable effects on those exhibiting lowMYClevels. Importantly, pharmacological inhibition of glutamine metabolism synergistically potentiated the synthetic lethaltargetingofMYCby 3-BrPA due in part to themetabolicdisturbance caused by this combination. Mechanistically, we identified that theproton-coupledmonocarboxylatetransporter 1 (MCT1) and MCT2, which enable efficient 3-BrPA uptake by cancer cells, were selectively activated byMyc. Two regulatory mechanisms were involved: first,Mycdirectly activated MCT1 and MCT2 transcription by binding to specific recognition sites of both genes; second,Myctranscriptionally repressed miR29a and miR29c, resulting in enhanced expression of their target protein MCT1. Of note, expressions of MCT1 and MCT2 were each significantly elevated in MYCN-amplified neuroblastomas and C-MYC-overexpressing lymphomas than in tumors withoutMYCoverexpression, correlating with poor prognosis and unfavorable patient survival. These results identify a novel mechanism by whichMycsensitizes cells tometabolicinhibitors and validate 3-BrPA as potentialMyc-selectivecancer therapeutics.Oncogeneadvance online publication, 5 October 2015; doi:10.1038/onc.2015.360.
