Abstract
Apoptosis induced by interferon-alpha (IFNa) is associated with induction of TRAIL in a number of different cell types. Here we examined whether or not TRAIL was required for apoptosis in a model human bladder cancer cell line (UM-UC-12) and defined the molecular mechanisms involved in IFNα-induced TRAIL expression. Exposure to IFNα resulted in concentration-dependent induction of TRAIL and apoptosis. Inhibition of TRAIL or downstream components of the TRAIL cell death pathway (FADD, caspase-8) via siRNA-mediated knockdown attenuated IFNα-induced cell death, thereby implicating TRAIL in the response. IFNαinduced rapid STAT-1 phosphorylation and DNA binding activity and subsequent accumulation of IRF-1. Transfection with siRNAs directed against STAT-1 or IRF-1 inhibited IFNα-induced TRAIL production and cell death, and chromatin immunprecipitation (ChIP) analyses demonstrated that IFNα induced direct, time-dependent binding of both transcription factors to the TRAIL promoter. Together, our results demonstrate that IFNα induces TRAIL expression via a STAT-1/IRF-1-dependent mechanism in human bladder cancer cells, and this induction of TRAIL plays an important role in IFNα-induced cell killing.
Original language | English (US) |
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Pages (from-to) | 872-879 |
Number of pages | 8 |
Journal | Cancer Biology and Therapy |
Volume | 6 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2007 |
Externally published | Yes |
Keywords
- Caspase-8
- ChIP
- FADD
- UM-UC-12
- siRNA
ASJC Scopus subject areas
- Molecular Medicine
- Oncology
- Pharmacology
- Cancer Research