Proteome and phosphoproteome reveal mechanisms of action of atorvastatin against esophageal squamous cell carcinoma.

Statins comprise a class of prescription drugs used for reducing cholesterol. Evidence has also showed that statins could reduce cancer incidence. However, the anti-tumor mechanism of statins has not been fully defined. Here, we found that atorvastatin inhibited proliferation of esophageal squamous cell carcinoma (ESCC) cells. The underlying mechanisms were explored by mass spectrometry. The proteome data revealed that atorvastatin inhibited the cAMP and Rap1 signal pathways, except for Ras signal pathway. Interestingly, phosphoproteome profiles suggested that ERK, CDK1, and BRAC1 phosphorylation-mediated Th17 cell differentiation, Gap junction and the Platinum drug resistance pathway were down-regulated after atorvastatin treatment. The phosphorylation levels of ERK, CDK1 and BRAC1 were confirmed by western blotting in KYSE150 cells. More importantly, atorvastatin suppresses ESCC tumor growth in PDX models. The molecular changes in tumor tissues were confirmed by immunohistochemistry. In conclusion, deep-proteome and phosphoproteome analysis reveal a comprehensive mechanism that contributes to atorvastatin's anti-tumor effect.