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Nat Genet. 2013 Jan;45(1):104-8. doi: 10.1038/ng.2471. Epub 2012 Dec 2.

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

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1
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

Abstract

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.

PMID:
23202129
PMCID:
PMC3530647
DOI:
10.1038/ng.2471
[Indexed for MEDLINE]
Free PMC Article

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