title: MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Kivanç
authors.initials: K
authors.lastname: Birsoy
authors.forename: Tim
authors.initials: T
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Possemato
authors.forename: Omer H
authors.initials: OH
authors.lastname: Yilmaz
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Koch
authors.forename: Walter W
authors.initials: WW
authors.lastname: Chen
authors.forename: Amanda W
authors.initials: AW
authors.lastname: Hutchins
authors.forename: Yetis
authors.initials: Y
authors.lastname: Gultekin
authors.forename: Tim R
authors.initials: TR
authors.lastname: Peterson
authors.forename: Jan E
authors.initials: JE
authors.lastname: Carette
authors.forename: Thijn R
authors.initials: TR
authors.lastname: Brummelkamp
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D027501:Monocarboxylic Acid Transporters / Q000235:genetics* / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism* / Q000494:pharmacology; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D027501:Monocarboxylic Acid Transporters; D011773:Pyruvates; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C017092:bromopyruvate