Knocking down galectin 1 in human hs683 glioblastoma cells impairs both angiogenesis and endoplasmic reticulum stress responses

J Neuropathol Exp Neurol. 2008 May;67(5):456-69. doi: 10.1097/NEN.0b013e318170f892.

Abstract

Galectin (Gal) 1 is a hypoxia-regulated proangiogenic factor that also directly participates in glioblastoma cell migration. To determine how Gal-1 exerts its proangiogenic effects, we investigated Gal-1 signaling in the human Hs683 glioblastoma cell line. Galectin 1 signals through the endoplasmic reticulum transmembrane kinase/ribonuclease inositol-requiring 1alpha, which regulates the expression of oxygen-regulated protein 150. Oxygen-regulated protein 150 controls vascular endothelial growth factor maturation. Galectin 1 also modulates the expression of 7 other hypoxia-related genes (i.e. CTGF, ATF3, PPP1R15A, HSPA5, TRA1, and CYR61) that are implicated in angiogenesis. Decreasing Gal-1 expression in Hs683 orthotopic xenografts in mouse brains by siRNA administration impaired endoplasmic reticulum stress and enhanced the therapeutic benefits of the proautophagic drug temozolomide. These results suggest that decreasing Gal-1 expression (e.g. through brain delivery of nonviral infusions of anti-Gal-1 siRNA in patients) can represent an additional therapeutic strategy for glioblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / therapy
  • Cell Line, Tumor
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / genetics*
  • Endoplasmic Reticulum / metabolism
  • Endoribonucleases / drug effects
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Female
  • Galectin 1 / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Silencing / physiology
  • Genetic Therapy / methods
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • Glioblastoma / therapy
  • HSP40 Heat-Shock Proteins / drug effects
  • HSP40 Heat-Shock Proteins / genetics
  • HSP40 Heat-Shock Proteins / metabolism
  • HSP70 Heat-Shock Proteins
  • Humans
  • Membrane Proteins / drug effects
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Chaperones / drug effects
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / therapy
  • Oxidative Stress / genetics*
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / drug effects
  • Proteins / genetics
  • Proteins / metabolism
  • RNA Interference / drug effects
  • RNA Interference / physiology*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • RNA, Small Interfering / therapeutic use
  • Signal Transduction / genetics
  • Temozolomide
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents, Alkylating
  • DNAJB9 protein, human
  • Galectin 1
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Membrane Proteins
  • Molecular Chaperones
  • Proteins
  • RNA, Small Interfering
  • oxygen-regulated proteins
  • Dacarbazine
  • ERN2 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • Temozolomide