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Abstract
BackgroundThere 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.ResultsHere, we identify monocarboxylate transporter 1 (MCT-1; encoded by SLC16A1) as a direct target gene supporting Wnt-driven Warburg metabolism. We identify and validate Wnt response elements (WREs) in the proximal SLC16A1 promoter 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 of SLC16A1 transcription. 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40170-016-0159-3) contains supplementary material, which is available to authorized users.
Highlights
There is increasing evidence that oncogenic Wnt signaling directs metabolic reprogramming of cancer cells to favor aerobic glycolysis or Warburg metabolism
monocarboxylate transporter 1 (MCT-1) is regulated by Wnt signaling Our recent discovery showing that Wnt signaling directs colon cancer cells to utilize glycolysis focused on Wnt regulation of target gene pyruvate dehydrogenase kinase 1 (PDK1), a mitochondrial kinase that suppresses pyruvate uptake by mitochondria to favor conversion to lactate in the cytoplasm
We focus on the lactate transporter SLC16A1/MCT-1 because it lies downstream of PDK1 and glycolysis to export metabolites such as lactate, and because it is the importer of 3-BP
Summary
There is increasing evidence that oncogenic Wnt signaling directs metabolic reprogramming of cancer cells to favor aerobic glycolysis or Warburg metabolism. Interference by these dominant-negative isoforms represses target gene transcription, and genome-wide expression analysis of downregulated transcription can reveal candidate target genes and the gene programs with which they are associated We used this type of analysis in colon cancer cells to discover that Wnt signaling promotes tumor cell preferences for aerobic glycolysis/Warburg metabolism, with the Wnt target gene pyruvate dehydrogenase kinase 1 (PDK1) playing a significant role in this metabolic fate [8]. QRT-PCR analysis of xenograft tumors from a colon cancer cell line showed MCT-1 downregulation in the presence of dnLEF/TCFs, and ChIP-seq ENCODE data shows TCF-4 occupancy of SLC16A1 in HCT116 colon cancer cells [8] These preliminary findings strongly implicate MCT-1 as a direct Wnt target gene that might be coordinately regulated with PDK1. We investigate this possibility and show that MCT-1/SLC16A1 is a direct target gene of β-catenin-LEF/TCF complexes in colon cancer cells
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