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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biological Transport / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycolysis / drug effects
  • Glycolysis / genetics
  • Humans
  • Mice
  • Mice, Nude
  • Monocarboxylic Acid Transporters / genetics*
  • Monocarboxylic Acid Transporters / metabolism
  • Pyruvates / metabolism*
  • Pyruvates / pharmacology
  • Symporters / genetics*
  • Symporters / metabolism

Substances

  • Monocarboxylic Acid Transporters
  • Pyruvates
  • Symporters
  • monocarboxylate transport protein 1
  • bromopyruvate