title: Lactate/pyruvate transporter MCT-1 is a direct Wnt target that confers sensitivity to 3-bromopyruvate in colon cancer.
abstract: BACKGROUND
  There is increasing evidence that oncogenic Wnt signaling directs metabolic reprogramming of cancer cells to favor aerobic glycolysis or Warburg metabolism. In colon cancer, this reprogramming is due to direct regulation of pyruvate dehydrogenase kinase 1 (PDK1) gene transcription. Additional metabolism genes are sensitive to Wnt signaling and exhibit correlative expression with PDK1. Whether these genes are also regulated at the transcriptional level, and therefore a part of a core metabolic gene program targeted by oncogenic WNT signaling, is not known.
  
  
  RESULTS
  Here, we identify monocarboxylate transporter 1 (MCT-1; encoded bySLC16A1) as a direct target gene supporting Wnt-driven Warburg metabolism. We identify and validate Wnt response elements (WREs) in the proximalSLC16A1promoter and show that they mediate sensitivity to Wnt inhibition via dominant-negative LEF-1 (dnLEF-1) expression and the small molecule Wnt inhibitor XAV939. We also show that WREs function in an independent and additive manner with c-Myc, the only other known oncogenic regulator ofSLC16A1transcription. MCT-1 can export lactate, the byproduct of Warburg metabolism, and it is the essential transporter of pyruvate as well as a glycolysis-targeting cancer drug, 3-bromopyruvate (3-BP). Using sulforhodamine B (SRB) assays to follow cell proliferation, we tested a panel of colon cancer cell lines for sensitivity to 3-BP. We observe that all cell lines are highly sensitive and that reduction of Wnt signaling by XAV939 treatment does not synergize with 3-BP, but instead is protective and promotes rapid recovery.
  
  
  CONCLUSIONS
  We conclude that MCT-1 is part of a core Wnt signaling gene program for glycolysis in colon cancer and that modulation of this program could play an important role in shaping sensitivity to drugs that target cancer metabolism.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sprowl-Tanio
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA USA.
authors.forename: Amber N
authors.initials: AN
authors.lastname: Habowski
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA USA.
authors.forename: Kira T
authors.initials: KT
authors.lastname: Pate
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA USA.
authors.forename: Miriam M
authors.initials: MM
authors.lastname: McQuade
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA USA.
authors.forename: Kehui
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Edwards
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Grun
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA USA.
authors.forename: Yung
authors.initials: Y
authors.lastname: Lyou
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA USA.
authors.forename: Marian L
authors.initials: ML
authors.lastname: Waterman
keywords: 3-Bromopyruvate; Colon cancer; Metabolism; Monocarboxylate transporter 1 (MCT-1); SLC16A1; Wnt signaling; XAV939