Angiopoietin-like protein 3 blocks nuclear import of FAK and contributes to sorafenib response

Br J Cancer. 2018 Aug;119(4):450-461. doi: 10.1038/s41416-018-0189-4. Epub 2018 Jul 23.

Abstract

Background: Poor drug response of sorafenib is a major challenge which reduces clinical benefit of renal cell carcinoma (RCC) patients. It is therefore of great clinical significance to elucidate the underlying mechanism to restore the therapeutic response to sorafenib.

Methods: Angiopoietin-like protein 3 (ANGPTL3) protein levels were measured by western blot and immunohistochemistry in two cohorts of RCC patients. Loss-of-function and gain-of-function experiments were performed to investigate the biological roles of ANGPTL3 in response to sorafenib treatment in RCC cells. Human proteome microarray and immunoprecipitation analysis were performed to explore the molecular mechanisms underlying the functions of ANGPTL3.

Results: ANGPTL3 was upregulated in sorafenib-responsive RCC, which correlated with clinically good sorafenib response. Knockdown of ANGPTL3 conferred sorafenib-tolerance traits to RCC cells, whereas overexpression of ANGPTL3 restored sorafenib sensitivity in RCC cells. Mechanistically, ANGPTL3 bound to Focal Adhesion Kinase(FAK) and restained sorafenib induced nuclear translocation of FAK, leading to attenuate the ubiquitination of p53, which contributed to cellular apoptosis and enhanced sorafenib response.

Conclusions: ANGPTL3 may be a novel predictor for the response of sorafenib therapy in RCC patients, and a potential target in improving its therapeutic effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Angiopoietin-like Proteins / metabolism*
  • Animals
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Focal Adhesion Kinase 1 / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Male
  • Mice
  • Sorafenib / administration & dosage*
  • Sorafenib / pharmacology
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitination
  • Up-Regulation*
  • Xenograft Model Antitumor Assays

Substances

  • ANGPTL3 protein, human
  • Angiopoietin-like Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Sorafenib
  • Focal Adhesion Kinase 1
  • PTK2 protein, human