Inhibition of Wnt Signaling by Atovaquone Inhibits Gastric Cancer and Enhances Chemotherapy Effectiveness Through Activation of Casein Kinase 1α

Abstract

Abnormal activation of the Wnt/β-catenin signaling pathway is a driving force behind the progression of gastric cancer. Atovaquone, known as an antimalarial drug, has emerged as a potential candidate for anti-cancer therapy. This study investigated atovaquone’s effects on gastric cancer and its underlying mechanisms. Using gastric cancer cell lines, we found that atovaquone, at concentrations relevant to clinical use, significantly reduced their viability. Notably, atovaquone exhibited a lower effectiveness in reducing the viability of normal gastric cells compared to gastric cancer cells. We further demonstrated that atovaquone inhibited gastric cancer growth and colony formation. Mechanism studies revealed that atovaquone inhibited mitochondrial respiration and induced oxidative stress. Experiments using ρ0 cells, deficient in mitochondrial respiration, indicated a slightly weaker effect of atovaquone on inducing apoptosis compared to wildtype cells. Atovaquone increased phosphorylated β-catenin at Ser45 and Ser33/37/Thr41, elevated Axin, and reduced β-catenin. The inhibitory effects of atovaquone on β-catenin were reversed upon depletion of CK1α. Furthermore, the combination of atovaquone with paclitaxel suppressed gastric cancer growth and improved overall survival in mice. Given that atovaquone is already approved for clinical use, these findings suggest its potential as a valuable addition to the drug arsenal available for treating gastric cancer.

Ethical Approval and Consent to Participate

This study was approved by the Ethics Committee of Renmin Hospital, Hubei University of Medicine.

Consent for Publication

Not applicable.

Disclosure Statement

No potential conflict of interest was reported by the author(s).

Data Availability Statement

Data and materials are available upon request.

Additional information

Funding

This study was supported by the Nature Science Foundation of Hubei Province (Grant No. 2017CFB606).