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

Nat Genet
Publication type
Journal Article
Authors
Keywords
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.

Year of Publication
2013
Journal
Nat Genet
Volume
45
Issue
1
Pages
104-8
Date Published
2013 Jan
ISSN
1546-1718
URL
DOI
10.1038/ng.2471
PubMed ID
23202129
PubMed Central ID
PMC3530647
Links
Grant list
K99 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