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.

中文翻译：

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乳酸/丙酮酸转运蛋白 MCT-1 是直接的 Wnt 靶标，可赋予结肠癌中对 3-溴丙酮酸的敏感性

背景越来越多的证据表明致癌 Wnt 信号引导癌细胞的代谢重编程，以促进有氧糖酵解或 Warburg 代谢。在结肠癌中，这种重编程是由于丙酮酸脱氢酶激酶 1 (PDK1) 基因转录的直接调节。其他代谢基因对 Wnt 信号敏感，并表现出与 PDK1 的相关表达。这些基因是否也在转录水平受到调节，因此是致癌 WNT 信号靶向的核心代谢基因程序的一部分，尚不清楚。 结果在这里，我们确定单羧酸转运蛋白 1（MCT-1；由 SLC16A1 编码）作为直接支持 Wnt 驱动的 Warburg 代谢的靶基因。我们鉴定并验证了近端 SLC16A1 启动子中的 Wnt 反应元件 (WRE)，并表明它们通过显性负性 LEF-1 (dnLEF-1) 表达和小分子 Wnt 抑制剂 XAV939 介导对 Wnt 抑制的敏感性。我们还表明 WRE 与 c-Myc 以独立和相加的方式起作用，c-Myc 是 SLC16A1 转录的唯一其他已知致癌调节剂。MCT-1 可以输出乳酸，这是 Warburg 代谢的副产物，它是丙酮酸的重要转运蛋白，也是一种靶向糖酵解的抗癌药物 3-溴丙酮酸 (3-BP)。我们使用磺基罗丹明 B (SRB) 检测来跟踪细胞增殖，测试了一组结肠癌细胞系对 3-BP 的敏感性。我们观察到所有细胞系都高度敏感，并且通过 XAV939 处理减少 Wnt 信号并不与 3-BP 协同作用，