Site-1 protease, a novel metabolic target for glioblastoma

Biochem Biophys Res Commun. 2017 Aug 26;490(3):760-766. doi: 10.1016/j.bbrc.2017.06.114. Epub 2017 Jun 20.

Abstract

Sterol regulatory element binding proteins (SREBPs) are transcriptional regulators of lipids which promote glioblastoma growth. Here, we investigate the effect of inhibiting expression of SREBP target genes in human glioblastoma cells. This was achieved by using PF-429242 to inhibit site-1 protease (S1P), an enzyme required for SREBP activation. Treatment with PF-429242 decreased glioblastoma cell viability, induced apoptosis and downregulated steroid, isoprenoid and unsaturated fatty acid biosynthetic pathways. Several pro-inflammatory genes were upregulated. Collectively, these results demonstrate the potential of S1P as a target for glioblastoma therapy.

Keywords: Cholesterol; Glioblastoma; PF-429242; Site-1 protease; Sterol regulatory element binding proteins (SREBPs).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • CHO Cells
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Cholesterol / metabolism
  • Cricetulus
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Humans
  • Lipid Metabolism / drug effects*
  • Molecular Targeted Therapy
  • Proprotein Convertases / antagonists & inhibitors*
  • Proprotein Convertases / metabolism
  • Pyrrolidines / pharmacology*
  • Serine Endopeptidases / metabolism
  • Sterol Regulatory Element Binding Protein 2 / metabolism
  • Sterol Regulatory Element Binding Proteins / metabolism*

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • PF-429242
  • Pyrrolidines
  • SREBF2 protein, human
  • Sterol Regulatory Element Binding Protein 2
  • Sterol Regulatory Element Binding Proteins
  • Cholesterol
  • Proprotein Convertases
  • Serine Endopeptidases
  • membrane-bound transcription factor peptidase, site 1