title: Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters.
abstract: Deregulation of the MYC oncogene produces Myc protein that regulates multiple aspects of cancer cell metabolism, contributing to the acquisition of building blocks essential for cancer cell growth and proliferation. Therefore, disabling Myc function represents an attractive therapeutic option for cancer treatment. However, pharmacological strategies capable of directly targeting Myc remain 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 the MYC oncogene, in vitro and in vivo, without appreciable effects on those exhibiting low MYC levels. Importantly, pharmacological inhibition of glutamine metabolism synergistically potentiated the synthetic lethal targeting of MYC by 3-BrPA due in part to the metabolic disturbance caused by this combination. Mechanistically, we identified that the proton-coupled monocarboxylate transporter 1 (MCT1) and MCT2, which enable efficient 3-BrPA uptake by cancer cells, were selectively activated by Myc. Two regulatory mechanisms were involved: first, Myc directly activated MCT1 and MCT2 transcription by binding to specific recognition sites of both genes; second, Myc transcriptionally 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 without MYC overexpression, correlating with poor prognosis and unfavorable patient survival. These results identify a novel mechanism by which Myc sensitizes cells to metabolic inhibitors and validate 3-BrPA as potential Myc-selective cancer therapeutics.
authors.affiliation: Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.|School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Gan
authors.affiliation: School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: R
authors.initials: R
authors.lastname: Xiu
authors.affiliation: School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: P
authors.initials: P
authors.lastname: Ren
authors.affiliation: School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: M
authors.initials: M
authors.lastname: Yue
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Su
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: G
authors.initials: G
authors.lastname: Guo
authors.affiliation: School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: D
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Key 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.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: Key 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.
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: G
authors.initials: G
authors.lastname: Hu
authors.affiliation: School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.|Medical Research Institute, Wuhan University, Wuhan, People's Republic of China.
authors.forename: G
authors.initials: G
authors.lastname: Qing
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D016259:Genes, myc; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D027981:Symporters / Q000378:metabolism*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D027501:Monocarboxylic Acid Transporters; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C489427:MYC protein, human; C490427:SLC16A7 protein, human; C517741:3-bromopyridine