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Nat Genet DOI:10.1038/ng.2471

MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors.

Publication TypeJournal Article
Year of Publication2013
AuthorsBirsoy, K, Wang, T, Possemato, R, Yilmaz, ÖH, Koch, CE, Chen, WW, Hutchins, AW, Gültekin, Y, Peterson, TR, Carette, JE, Brummelkamp, TR, Clish, CB, Sabatini, DM
JournalNat Genet
Date Published2013 Jan
KeywordsAnimals, Biological Transport, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Glycolysis, Humans, Mice, Mice, Nude, Monocarboxylic Acid Transporters, Pyruvates, Symporters

There is increasing evidence that oncogenic transformation modifies the metabolic program of cells. A common alteration is the upregulation of glycolysis, and efforts to target glycolytic enzymes for anticancer therapy are under way. Here, we performed a genome-wide haploid genetic screen to identify resistance mechanisms to 3-bromopyruvate (3-BrPA), a drug candidate that inhibits glycolysis in a poorly understood fashion. We identified the SLC16A1 gene product, MCT1, as the main determinant of 3-BrPA sensitivity. MCT1 is necessary and sufficient for 3-BrPA uptake by cancer cells. Additionally, SLC16A1 mRNA levels are the best predictor of 3-BrPA sensitivity and are most elevated in glycolytic cancer cells. Furthermore, forced MCT1 expression in 3-BrPA-resistant cancer cells sensitizes tumor xenografts to 3-BrPA treatment in vivo. Our results identify a potential biomarker for 3-BrPA sensitivity and provide proof of concept that the selectivity of cancer-expressed transporters can be exploited for delivering toxic molecules to tumors.


Alternate JournalNat. Genet.
PubMed ID23202129
PubMed Central IDPMC3530647
Grant ListK99 AG045144 / AG / NIA NIH HHS / United States
R01 CA103866 / CA / NCI NIH HHS / United States
CA103866 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States