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

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.

Transcriptome Profiling of Toxoplasma gondii-Infected Human Cerebromicrovascular Endothelial Cell Response to Treatment with Monensin

“…This finding is consistent with the upregulation of the DNA damage-inducible transcript 3 (DDIT3), a key gene in the upregulated pathway, which encodes a stress-inducible transcription factor that induces cell cycle arrest and apoptosis in mammalian cells. Our finding is consistent with a previous study that showed that monensin induced DDIT3, a key inhibitor of the Wnt signalling pathway [42], in prostate cancer cells [43]. The key genes identified in those downregulated pathways are CCNA2, that controls both the G1/S and the G2/M transition phases of the cell cycle, and MYBL2, that functions as a physiological regulator of cell cycle progression.…”

Intracellular pH controls Wnt signaling downstream of glycolysis in the vertebrate embryo

“…Our data is also consistent with posterior PSM and tail bud cells exhibiting Warburg-like metabolism with high aerobic glycolysis and an inverted pHe/pHi gradient as compared to more differentiated cells. Decreasing the pHi in Wnt-addicted tumor cells was recently shown to inhibit Wnt signaling, as reported here for differentiating tail bud cells (26). Thus our findings further emphasize the tight similarity between the developing tail bud cell and cancer cells that exhibit high Warburg metabolism resulting in high pHi and low pHe (27), supporting the notion that some tumor cells might reactivate a developmental metabolic program.…”

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

“…Boosting glycolysis with mitochondria inhibitors such as Metformin (MET) have also been proposed to be a method to decrease pHi in various cancer cell lines, BC among them [96], alone and/or in combination with the MCT inhibitor Simvastatin [97] ( Table 2).…”

“…MET has been proposed to be a viable anticancer drug since it induces intracellular hyperacidification in tumor xenograft models through inhibition of Wnt signaling, a feature found to be selective for cancer cells [96]. During the last few years MET has been introduced as an anticancer agent in clinical oncology after it was reported to decrease mortality of BC patients [236,237,[246][247][248], increasing the survival of triple-negative BC patients [248] .…”