MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors
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 identif...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2013
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| Online Access: | http://hdl.handle.net/1721.1/79435 https://orcid.org/0000-0002-4227-5163 https://orcid.org/0000-0002-2401-0030 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0002-7577-4612 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0002-1751-7327 |
| _version_ | 1810992407765843968 |
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| author | Birsoy, Kivanc Wang, Tim Possemato, Richard Koch, Catherine E. Chen, Walter W. Hutchins, Amanda W. Gultekin, Yetis Carette, Jan E. Brummelkamp, Thijn R. Clish, Clary Yilmaz, Omer Peterson, Timothy Richard Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Birsoy, Kivanc Wang, Tim Possemato, Richard Koch, Catherine E. Chen, Walter W. Hutchins, Amanda W. Gultekin, Yetis Carette, Jan E. Brummelkamp, Thijn R. Clish, Clary Yilmaz, Omer Peterson, Timothy Richard Sabatini, David |
| author_sort | Birsoy, Kivanc |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:09:06Z |
| format | Article |
| id | mit-1721.1/79435 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:09:06Z |
| publishDate | 2013 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/794352022-09-28T12:14:01Z MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors Birsoy, Kivanc Wang, Tim Possemato, Richard Koch, Catherine E. Chen, Walter W. Hutchins, Amanda W. Gultekin, Yetis Carette, Jan E. Brummelkamp, Thijn R. Clish, Clary Yilmaz, Omer Peterson, Timothy Richard Sabatini, David Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Sabatini, David M. Sabatini, David M. Birsoy, Kivanc Wang, Tim Possemato, Richard Yilmaz, Omer H. Koch, Catherine E. Chen, Walter W. Hutchins, Amanda W. Gultekin, Yetis Peterson, Tim R. 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. National Institutes of Health (U.S.) (NIH CA103866) Jane Coffin Childs Memorial Fund for Medical Research (Fellowship) National Science Foundation (U.S.) (Fellowship) Howard Hughes Medical Institute (Investigator) 2013-07-10T14:30:10Z 2013-07-10T14:30:10Z 2012-12 2012-07 Article http://purl.org/eprint/type/JournalArticle 1061-4036 1546-1718 http://hdl.handle.net/1721.1/79435 Birsoy, Kivanç, Tim Wang, Richard Possemato, Omer H Yilmaz, Catherine E Koch, Walter W Chen, Amanda W Hutchins, et al. MCT1-mediated Transport of a Toxic Molecule Is an Effective Strategy for Targeting Glycolytic Tumors. Nature Genetics 45, no. 1 (December 2, 2012): 104-108. https://orcid.org/0000-0002-4227-5163 https://orcid.org/0000-0002-2401-0030 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0002-7577-4612 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0002-1751-7327 en_US http://dx.doi.org/10.1038/ng.2471 Nature Genetics Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group Sabatini via Courtney Crummett |
| spellingShingle | Birsoy, Kivanc Wang, Tim Possemato, Richard Koch, Catherine E. Chen, Walter W. Hutchins, Amanda W. Gultekin, Yetis Carette, Jan E. Brummelkamp, Thijn R. Clish, Clary Yilmaz, Omer Peterson, Timothy Richard Sabatini, David MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors |
| title | MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors |
| title_full | MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors |
| title_fullStr | MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors |
| title_full_unstemmed | MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors |
| title_short | MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors |
| title_sort | mct1 mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors |
| url | http://hdl.handle.net/1721.1/79435 https://orcid.org/0000-0002-4227-5163 https://orcid.org/0000-0002-2401-0030 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0002-7577-4612 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0002-1751-7327 |
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