2. Academic Validation
  3. Quantitative proteomics identifies FOLR1 to drive sorafenib resistance via activating autophagy in hepatocellular carcinoma cells

Quantitative proteomics identifies FOLR1 to drive sorafenib resistance via activating autophagy in hepatocellular carcinoma cells

  • Carcinogenesis. 2021 May 28;42(5):753-761. doi: 10.1093/carcin/bgab019.
Hongwei Chu 1 2,  Changqing Wu 2 3,  Qun Zhao 2,  Rui Sun 2,  Kuo Yang 4,  Baofeng Zhao 2,  Yang Liu 2 5,  Zhen Liang 2,  Shijun Zhong 6,  Lihua Zhang 2,  Yukui Zhang 1 2
Affiliations

Affiliations

  • 1 Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, China.
  • 2 CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China.
  • 3 Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, China.
  • 4 BNRIST/Department of Automation, Tsinghua University, Beijing, China.
  • 5 Innovative Research Center for Integrated Cancer Omics, the Second Hospital Affiliated to China Medical University, Shenyang, China.
  • 6 School of Bioengineering, Dalian University of Technology, Dalian, China.
PMID: 33677528 DOI: 10.1093/carcin/bgab019
Abstract

Sorafenib is commonly used to treat advanced human hepatocellular carcinoma (HCC). However, clinical efficacy has been limited by drug resistance. In this study, we used label-free quantitative proteomic analysis to systematically investigate the underlying mechanisms of sorafenib resistance in HCC cells. A total of 1709 proteins were confidently quantified. Among them, 89 were differentially expressed and highly enriched in the processes of cell-cell adhesion, negative regulation of Apoptosis, response to drug and metabolic processes involving in sorafenib resistance. Notably, folate receptor α (FOLR1) was found to be significantly upregulated in resistant HCC cells. In addition, in vitro studies showed that overexpression of FOLR1 decreased the sensitivity of HCC cells to sorafenib, whereas siRNA-directed knockdown of FOLR1 increased the sensitivity of HCC cells to sorafenib. Immunoprecipitation-mass spectrometry analysis suggested a strong link between FOLR1 and autophagy-related proteins. Further biological experiments found that FOLR1-related sorafenib resistance was accompanied by the activation of Autophagy, whereas inhibition of Autophagy significantly reduced FOLR1-induced cell resistance. These results suggest the driving role of FOLR1 in HCC resistance to sorafenib, which may be exerted through FOLR1-induced Autophagy. Therefore, this study may provide new insights into understanding the mechanism of sorafenib resistance.

Figures
Products