IFN-γ sensitization of prostate cancer cells to Fas-mediated death: A gene therapy approach

William A. Selleck, Steven E. Canfield, Waleed A. Hassen, Marcia Meseck, Alexei I. Kuzmin, Randy C. Eisensmith, Shu Hsia Chen, Simon J. Hall

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

While human prostate cancers and cell lines express Fas, most of these cell lines are resistant to Fas-mediated death. In the present studies we addressed the ability of IFN-γ to influence Fas-mediated cell death in prostate cancer cells. In vitro exposure of the human cell lines LNCaP and PC3 and the mouse cell line RM-1 to agonist anti-Fas antibody and/or soluble Fas ligand resulted in killing of only PC3 cells. However, preincubation with IFN-γ resulted in synergistic killing in all three cell lines. In vitro treatment of RM-1 with a replication-incompetent adenovirus expressing mouse FasL (Ad.FasL) resulted in maximal cell kill near 40%, which correlated with baseline Fas expression. The addition of IFN-γ enhanced cell kill to a degree consistent with the resulting higher levels of Fas and maintained synergistic killing at very low doses of vector. Co-inoculation of orthotopic RM-1 primary tumors with Ad.mFasL and an adenovirus expressing mouse IL-12 (Ad.mIL-12) to drive host production of IFN-γ negated the survival advantage of Ad.mIL-12 alone. However, the staggered injection of Ad.mIL-12 and Ad.FasL achieved almost threefold higher levels of apoptosis in primary tumor tissue and doubled median survival. Therefore, IFN-γ is capable of bestowing increased sensitivity to Fas-mediated cell death in prostate cancer cells and, in a gene therapy approach, may define a powerful tool to treat prostate cancers.

Original languageEnglish (US)
Pages (from-to)185-192
Number of pages8
JournalMolecular Therapy
Volume7
Issue number2
DOIs
StatePublished - Feb 1 2003

Keywords

  • Fas
  • FasL
  • Gene therapy
  • IFN-γ
  • IL-12
  • Prostate cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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