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

Nature Genetics volume 45, pages 104108 (2013) | Download Citation

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.

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Acknowledgements

We thank members of the Sabatini laboratory and F. Reinhardt for advice and assistance. This work was supported by grants from the US National Institutes of Health (NIH; CA103866) and the David H. Koch Institute for Integrative Cancer Research to D.M.S. and fellowships from the Jane Coffin Childs Memorial Fund to K.B. and US National Science Foundation to T.W. D.M.S. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

    • Jan E Carette
    •  & Thijn R Brummelkamp

    Present addresses: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA (J.E.C.) and Department of Biochemistry, Netherlands Cancer Institute, Amsterdam, The Netherlands (T.R.B.).

Affiliations

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

    • Kivanç Birsoy
    • , Tim Wang
    • , Richard Possemato
    • , Omer H Yilmaz
    • , Catherine E Koch
    • , Walter W Chen
    • , Amanda W Hutchins
    • , Yetis Gultekin
    • , Tim R Peterson
    • , Jan E Carette
    • , Thijn R Brummelkamp
    •  & David M Sabatini
  2. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.

    • Kivanç Birsoy
    • , Tim Wang
    • , Richard Possemato
    • , Omer H Yilmaz
    • , Catherine E Koch
    • , Walter W Chen
    • , Amanda W Hutchins
    • , Yetis Gultekin
    • , Tim R Peterson
    •  & David M Sabatini
  3. Broad Institute, Cambridge, Massachusetts, USA.

    • Kivanç Birsoy
    • , Tim Wang
    • , Richard Possemato
    • , Omer H Yilmaz
    • , Walter W Chen
    • , Amanda W Hutchins
    • , Yetis Gultekin
    • , Tim R Peterson
    • , Clary B Clish
    •  & David M Sabatini
  4. David H Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.

    • Kivanç Birsoy
    • , Tim Wang
    • , Richard Possemato
    • , Omer H Yilmaz
    • , Walter W Chen
    • , Amanda W Hutchins
    • , Yetis Gultekin
    • , Tim R Peterson
    •  & David M Sabatini
  5. Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts, USA.

    • David M Sabatini

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Contributions

K.B. and D.M.S. conceived the project. K.B. designed and performed most experiments and data analyses, with input from D.M.S. T.W. assisted with initial experiments and data analysis. C.E.K., O.H.Y., R.P., W.W.C., Y.G. and A.W.H. assisted with experiments, and T.R.P., J.E.C. and T.R.B. assisted with haploid genetic screening. C.B.C. performed metabolite profiling and analysis. K.B. and D.M.S. wrote and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David M Sabatini.

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DOI

https://doi.org/10.1038/ng.2471

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