Fig. 6: A mechanism of Wnt/β-catenin signaling repression by treatment with MCI inhibitor and H+ ionophore combination. | Cell Discovery

Fig. 6: A mechanism of Wnt/β-catenin signaling repression by treatment with MCI inhibitor and H+ ionophore combination.

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

Fig. 6

Without treatment (upper cell), Wnt/β-catenin signaling can be triggered either with Wnt ligand, or by inactivating APC mutation, or with stabilizing β-catenin mutation, all leading to β-catenin accumulation. β-catenin binds LEF/TCF transcription factors and induces target genes. Intracellular input of acid produced by weak leakage of protons through the cell membrane and due to glycolysis is compensated by the ATP-dependent H+ pumps. The proton pumps are fueled with the ATP produced by glycolysis and the TCA cycle in mitochondria. Once drug combination is applied (lower cell), upon a treatment with ionophore, leakage of protons from outside increases. Simultaneously, ATP production by the TCA cycle in mitochondria is reduced due to MCI inhibition. Compensatory increase of glycolysis produces even more acid causing acidification of intracellular compartment and thus, more ATP consumption that leads to ATP deficit. The resulting condition induces ER stress and the UPR, including transient DDIT3 induction. DDIT3 prevents β-catenin/LEF/TCF complex formation and its interaction with promoters of target genes leading to blockage of Wnt/β-catenin signaling, despite of β-catenin accumulation. If intracellular acidification and ATP depletion persist, DDIT3 induces apoptosis and death of cancer cells

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