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G1P3, an IFN-induced survival factor, antagonizes TRAIL-induced apoptosis in human myeloma cells

Venugopalan Cheriyath1, Keith B Glaser, Jeffrey F Waring

  • 1Center for Hematology and Oncology Molecular Therapeutics, The Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio, USA.

The Journal of Clinical Investigation
|September 8, 2007
PubMed

Insights

Interferon-alpha2b (IFN-alpha2b) shows variable effectiveness in multiple myeloma. A prosurvival gene, G1P3, antagonizes TRAIL-induced apoptosis by stabilizing mitochondria, suggesting new therapeutic targets.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • The effectiveness of Interferon-alpha2b (IFN-alpha2b) in treating human multiple myeloma is inconsistent.
  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been implicated in IFN-alpha2b-induced apoptosis in myeloma cells.

Purpose of the Study:

  • To investigate the impact of IFN-alpha2b signaling on TRAIL's apoptotic activity and multiple myeloma cell survival.
  • To identify Interferon-stimulated genes (ISGs) that may counteract TRAIL-mediated apoptosis.

Main Methods:

  • Assessed IFN-alpha2b effects on TRAIL-induced apoptosis in myeloma cell lines and primary cells.
  • Investigated the role of the ISG G1P3 in modulating apoptosis using ectopic expression and RNA interference (RNAi).
  • Analyzed mitochondrial function, caspase-3 activation, and cytochrome c release.

Main Results:

  • IFN-alpha2b induced TRAIL as a proapoptotic gene, but less than 20% of myeloma cells underwent apoptosis.
  • IFN-alpha2b stabilized mitochondria and inhibited caspase-3 activation, counteracting TRAIL-mediated apoptosis.
  • Induced expression of G1P3 correlated with IFN-alpha2b's antiapoptotic activity and was localized to mitochondria, inhibiting the intrinsic apoptosis pathway.
  • Downregulation of G1P3 restored IFN-alpha2b-induced apoptosis.

Conclusions:

  • A prosurvival ISG, G1P3, directly antagonizes TRAIL-mediated apoptosis by targeting the intrinsic mitochondrial pathway.
  • Targeting G1P3-mediated antiapoptotic signals may enhance the efficacy of IFN-alpha2b and TRAIL-based therapies for multiple myeloma and other cancers.

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