CUL5 is required for thalidomide-dependent inhibition of cellular proliferation

PLoS One. 2018 May 10;13(5):e0196760. doi: 10.1371/journal.pone.0196760. eCollection 2018.

Abstract

Angiogenesis is essential for cancer metastasis, thus the discovery and characterization of molecules that inhibit this process is important. Thalidomide is a teratogenic drug which is known to inhibit angiogenesis and effectively inhibit cancer metastasis, yet the specific cellular targets for its effect are not well known. We discovered that CUL5 (previously identified as VACM-1), a scaffold protein in E3 ligase complexes, is involved in thalidomide-dependent inhibition of endothelial cell growth. Our results show that in human endothelial cells (HUVEC), thalidomide-dependent decrease in cell growth was associated with decreased nuclear localization of CUL5. In HUVEC transfected with anti-VACM-1 siRNA, thalidomide failed to decrease cell growth. Previously it was established that the antiproliferative effect of CUL5 is inhibited in rat endothelial cells (RAMEC) transfected with mutated CUL5 which is constitutively modified by NEDD8, a ubiquitin-like protein. In this study, the antiproliferative response to thalidomide was compromised in RAMEC expressing mutated CUL5. These results suggest that CUL5 protein is involved in the thalidomide-dependent regulation of cellular proliferation in vitro. Consequently, CUL5 may be an important part of the mechanism for thalidomide-dependent inhibition of cellular proliferation, as well as a novel biomarker for predicting a response to thalidomide for the treatment of disorders such as multiple myeloma and HIV infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Cullin Proteins / metabolism*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • HIV Infections / drug therapy
  • HIV Infections / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism
  • RNA, Small Interfering / metabolism
  • Thalidomide / pharmacology*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Biomarkers
  • CUL5 protein, human
  • Cullin Proteins
  • RNA, Small Interfering
  • Thalidomide
  • Ubiquitin-Protein Ligases