Melnik Svitlana, Dvornikov Dmytro, Müller-Decker Karin, Depner Sofia, Stannek Peter, Meister Michael, Warth Arne, Thomas Michael, Muley Tomas, Risch Angela, Plass Christoph, Klingmüller Ursula, Niehrs Christof, Glinka Andrey
1Division of Epigenetics and Cancer Risks Factors, German Cancer Research Center, Heidelberg, D-69120 Germany.
2DNA vectors, German Cancer Research Center, Heidelberg, D-69120 Germany.
Cell Discov. 2018 Jul 3;4:37. doi: 10.1038/s41421-018-0033-2. eCollection 2018.
Use of the diabetes type II drug Metformin is associated with a moderately lowered risk of cancer incidence in numerous tumor entities. Studying the molecular changes associated with the tumor-suppressive action of Metformin we found that the oncogene , which is upregulated in solid tumors and associated with poor prognosis, was induced by Wnt/β-catenin signaling and blocked by Metformin. Wnt signaling inhibition by Metformin was surprisingly specific for cancer cells. Unraveling the underlying specificity, we identified Metformin and other Mitochondrial Complex I (MCI) inhibitors as inducers of intracellular acidification in cancer cells. We demonstrated that acidification triggers the unfolded protein response to induce the global transcriptional repressor , known to block Wnt signaling. Moreover, our results suggest that intracellular acidification universally inhibits Wnt signaling. Based on these findings, we combined MCI inhibitors with H ionophores, to escalate cancer cells into intracellular hyper-acidification and ATP depletion. This treatment lowered intracellular pH both in vitro and in a mouse xenograft tumor model, depleted cellular ATP, blocked Wnt signaling, downregulated , and strongly decreased stemness and viability of cancer cells. Importantly, the inhibition of Wnt signaling occurred downstream of β-catenin, encouraging applications in treatment of cancers caused by and mutations.
使用II型糖尿病药物二甲双胍与多种肿瘤实体的癌症发病率适度降低相关。在研究与二甲双胍的肿瘤抑制作用相关的分子变化时，我们发现，在实体瘤中上调且与预后不良相关的致癌基因是由Wnt/β-连环蛋白信号传导诱导，并被二甲双胍阻断。二甲双胍对Wnt信号传导的抑制作用对癌细胞具有惊人的特异性。在揭示其潜在特异性的过程中，我们确定二甲双胍和其他线粒体复合物I（MCI）抑制剂是癌细胞内酸化的诱导剂。我们证明，酸化会触发未折叠蛋白反应，以诱导已知可阻断Wnt信号传导的全局转录抑制因子。此外，我们的结果表明，细胞内酸化普遍抑制Wnt信号传导。基于这些发现，我们将MCI抑制剂与H离子载体联合使用，以使癌细胞进入细胞内过度酸化和ATP耗竭状态。这种处理在体外和小鼠异种移植肿瘤模型中均降低了细胞内pH值，耗尽了细胞ATP，阻断了Wnt信号传导，下调了相关基因，并强烈降低了癌细胞的干性和活力。重要的是，Wnt信号传导的抑制发生在β-连环蛋白的下游，这为治疗由相关基因突变引起的癌症提供了应用前景。
