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

Cell Discov 2018 3;4:37. Epub 2018 Jul 3.

Division of Molecular Embryology, DKFZ-ZMBH Allianz, German Cancer Research Center, Heidelberg, D-69120 Germany.

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.

Download full-text PDF

Source
http://www.nature.com/articles/s41421-018-0033-2
Publisher Site
http://dx.doi.org/10.1038/s41421-018-0033-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028397PMC
July 2018
68 Reads

Publication Analysis

Top Keywords

wnt signaling
20
cancer cells
16
intracellular acidification
12
wnt/β-catenin signaling
8
mci inhibitors
8
signaling
7
cancer
6
wnt
5
metformin
5
intracellular
5
inhibitors inducers
4
complex mci
4
metformin mitochondrial
4
mitochondrial complex
4
acidification cancer
4
acidification triggers
4
blocked wnt
4
triggers unfolded
4
demonstrated acidification
4
cells demonstrated
4

References

(Supplied by CrossRef)

YS Jung et al.
J. Gastroenterol. Hepatol. 2017

D Benjamin et al.
Sci. Adv. 2016

F Morgillo et al.
Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res. 2013

J Liu et al.
Oncol. Rep. 2012

NAB Samsuri et al.
Cancer Treat. Rev. 2017

S Zhong et al.
Indian J. Cancer 2017

Y Xiao et al.
Oncotarget 2017

W Xie et al.
Oncotarget 2017

AB Parikh et al.
Investig. New Drugs 2017

CW Song et al.
Sci. Rep. 2012

W Li et al.
Oncotarget 2015

Similar Publications