Thrombospondin-1 counteracts the p97 inhibitor CB-5083 in colon carcinoma cells

Cell Cycle. 2020 Jul;19(13):1590-1601. doi: 10.1080/15384101.2020.1754584. Epub 2020 May 19.

Abstract

p97 has recently emerged as a therapeutic target for cancer due to its essential functions in protein homeostasis. CB-5083 is a first-in-class, potent and selective ATP-competitive p97 inhibitor that induces proteotoxic stress in cancer cells. Potential mechanisms regulating the sensitivity of cells to p97 inhibition remain poorly studied. Here, we demonstrate that Thrombospondin-1 (THBS1) is a CB-5083-upregulated gene that helps confer resistance of HCT116 cells to CB-5083. Our immunoblotting and immunofluorescence data showed that CB-5083 significantly increases the steady-state abundance of THBS1. Blockade of THBS1 induction sensitized cells to CB-5083-mediated growth inhibition. Suppression of THBS1 caused an increase of CB-5083-induced sub-G1 population and caspase 3/7 activity suggesting that its function is linked to the survival of cancer cells in response to p97 inhibition. Altogether our data provide new evidence that THBS1 is important for the susceptibility of cells to p97 inhibition.

Keywords: Thrombospondin-1; cb-5083; p97; protein homeostasis.

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Indoles / pharmacology*
  • Pyrimidines / pharmacology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / metabolism*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • Valosin Containing Protein / antagonists & inhibitors*
  • Valosin Containing Protein / metabolism

Substances

  • CB-5083
  • Indoles
  • Pyrimidines
  • RNA, Messenger
  • Thrombospondin 1
  • Valosin Containing Protein