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MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors.
|Publication Type||Journal Article|
|Authors||Birsoy, K., Wang T., Possemato R., Yilmaz OH, Koch CE, Chen WW, Hutchins AW, Gultekin Y., Peterson TR, Carette JE, Brummelkamp TR, Clish CB, and Sabatini DM|
|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|
|Date Published (YYYY/MM/DD)||2013/01/01|