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

Overview of attention for article published in Cell Discovery, July 2018
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4 X users

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68 Mendeley
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Title
Cancer cell specific inhibition of Wnt/β-catenin signaling by forced intracellular acidification
Published in
Cell Discovery, July 2018
DOI 10.1038/s41421-018-0033-2
Pubmed ID
Authors

Svitlana Melnik, Dmytro Dvornikov, Karin Müller-Decker, Sofia Depner, Peter Stannek, Michael Meister, Arne Warth, Michael Thomas, Tomas Muley, Angela Risch, Christoph Plass, Ursula Klingmüller, Christof Niehrs, Andrey Glinka

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.

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The data shown below were collected from the profiles of 4 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 68 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 68 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 15 22%
Student > Bachelor 10 15%
Researcher 9 13%
Other 6 9%
Student > Master 5 7%
Other 8 12%
Unknown 15 22%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 20 29%
Medicine and Dentistry 8 12%
Pharmacology, Toxicology and Pharmaceutical Science 5 7%
Agricultural and Biological Sciences 4 6%
Immunology and Microbiology 4 6%
Other 8 12%
Unknown 19 28%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 October 2018.
All research outputs
#13,515,285
of 23,317,888 outputs
Outputs from Cell Discovery
#292
of 553 outputs
Outputs of similar age
#165,537
of 328,556 outputs
Outputs of similar age from Cell Discovery
#11
of 20 outputs
Altmetric has tracked 23,317,888 research outputs across all sources so far. This one is in the 41st percentile – i.e., 41% of other outputs scored the same or lower than it.
So far Altmetric has tracked 553 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 37.1. This one is in the 46th percentile – i.e., 46% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 328,556 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 48th percentile – i.e., 48% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 20 others from the same source and published within six weeks on either side of this one. This one is in the 45th percentile – i.e., 45% of its contemporaries scored the same or lower than it.