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Cell Discov. 2018 Jul 3;4:37. doi: 10.1038/s41421-018-0033-2. eCollection 2018.

Cancer cell specific inhibition of Wnt/β-catenin signaling by forced intracellular acidification.

Author information

1
1Division of Epigenetics and Cancer Risks Factors, German Cancer Research Center, Heidelberg, D-69120 Germany.
2
2DNA vectors, German Cancer Research Center, Heidelberg, D-69120 Germany.
3
3Division of Systems Biology and Signal Transduction, German Cancer Research Center, Heidelberg, D-69120 Germany.
4
4Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
5
5Tumor Models Unit, Center for Preclinical Research, German Cancer Research Center, Heidelberg, D-69120 Germany.
6
Division of Molecular Embryology, DKFZ-ZMBH Allianz, German Cancer Research Center, Heidelberg, D-69120 Germany.
7
7Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Heidelberg, D-69126 Germany.
8
8Institute of Pathology, Heidelberg University Hospital, Heidelberg, 69120 Germany.
9
9Department of Molecular Biology, University of Salzburg, Salzburg, 5020 Austria.
10
Cancer Cluster Salzburg, Salzburg, 5020 Austria.
11
11Institute of Molecular Biology (IMB), Mainz, 55128 Germany.
#
Contributed equally

Abstract

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 SOX4, 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 DDIT3, 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 SOX4, 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 APC and β-catenin mutations.

Conflict of interest statement

SM, DD, CN, and AG are inventors on a patent application EP16174558. Other authors declare no competing financial interest.

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