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GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib

Johann Kern1, Gerold Untergasser, Christoph Zenzmaier

  • 1Tumor Biology & Angiogenesis Laboratory, Department of Internal Medicine V, Innsbruck Medical University, Innsbruck, Austria.

Blood
|August 29, 2009
PubMed

Insights

Solid tumor cells secrete GRP-78, a protein that confers resistance to the proteasome inhibitor bortezomib. This discovery reveals a new mechanism of bortezomib resistance in cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The proteasome inhibitor bortezomib is used in cancer therapy.
  • Bortezomib's antiangiogenic effects are crucial for its efficacy.
  • Mechanisms of bortezomib resistance in solid tumors require further elucidation.

Purpose of the Study:

  • To investigate the mechanisms underlying bortezomib resistance in solid tumors.
  • To identify factors secreted by tumor cells that mediate resistance to bortezomib.
  • To explore the role of GRP-78 in bortezomib resistance and its impact on tumor vascularization.

Main Methods:

  • In vivo studies using tumor xenografts and the chicken chorioallantoic membrane model.
  • Biochemical analyses including size-exclusion and ion-exchange chromatography, and mass spectrometry.
  • Gene knockdown and protein immunodepletion experiments to assess GRP-78 function.
  • Analysis of intracellular signaling pathways, including extracellular signal-related kinase and p53-mediated apoptosis.

Main Results:

  • Bortezomib effectively inhibited angiogenesis in the chicken chorioallantoic membrane model.
  • Tumor xenografts abrogated bortezomib's antiangiogenic effects via a secreted soluble factor.
  • GRP-78 was identified as the secreted factor responsible for bortezomib resistance in solid tumor cells.
  • Recombinant GRP-78 conferred bortezomib resistance to endothelial and myeloma cells.
  • GRP-78 promoted cell survival by activating prosurvival signals and inhibiting proapoptotic pathways.

Conclusions:

  • Solid tumor cells secrete GRP-78, a chaperone protein, which confers resistance to bortezomib.
  • GRP-78 mediates resistance by inducing prosurvival signals and inhibiting apoptosis, independent of direct bortezomib binding.
  • This study identifies a novel mechanism of bortezomib resistance involving GRP-78 secretion into the tumor microenvironment.

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