Research Paper Volume 11, Issue 21 pp 9530—9543

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

Qiang Yuan 1, 2, , Christopher D. Dong 3, , Yang Ge 4, , Xinhuan Chen 1, , Zhenzhen Li 1, 2, , Xin Li 1, 5, , Qiqi Lu 1, 2, , Feng Peng 1, 2, , Xiangyu Wu 1, 2, , Jimin Zhao 1, 5, , Kangdong Liu 1, 2, 5, 6, 7, ,

  • 1 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
  • 2 China-US Hormel (Henan) Cancer Institute, Zhengzhou, Henan, China
  • 3 Wartburg College, Waverly, IA 50677, USA
  • 4 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • 5 Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, China
  • 6 Henan Provincial Key Laboratory of Esophageal Cancer, Zhengzhou, Henan, China
  • 7 Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China

received: August 7, 2019 ; accepted: October 26, 2019 ; published: November 7, 2019 ;

https://doi.org/10.18632/aging.102402
How to Cite

Copyright © 2019 Yuan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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 ERKT185/Y187, CDK1T14, and BRAC1S1189 phosphorylation–mediated Th17 cell differentiation, Gap junction and the Platinum drug resistance pathway were down-regulated after atorvastatin treatment. The phosphorylation levels of ERKT185/Y187, CDK1T14 and BRAC1S1189 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.

Abbreviations

ESCC: Esophageal squamous cell carcinoma; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomics; MS: Mass spectrometry; PDX: Patient-derived xenograft; ppm: parts per million.