FAP-1-mediated activation of NF-κB induces resistance of head and neck cancer to fas-induced apoptosis

✍ Scribed by Eva Wieckowski; Yoshinari Atarashi; Joanna Stanson; Taka-Aki Sato; Theresa L. Whiteside

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 280 KB
• Volume: 100
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.20922

✦ Synopsis

Abstract

Molecular mechanisms responsible for tumor resistance to apoptosis often involve the Fas/FasL pathway. While squamous cell carcinomas of the head and neck (SCCHN) express both Fas and FasL, their resistance to self‐induced apoptosis or apoptosis mediated by Fas agonistic antibody (CH‐11Ab) was independent of the level of Fas surface expression or the presence of soluble Fas in supernatants of primary or metastatic SCCHN cell lines. By in vitro immunoselection, using PCI‐15A cell line treated with successive cycles of CH‐11 Ab, Fas‐resistant sublines with the parental genotype were selected. Such sublines failed to cleave caspase‐8 upon Fas engagement and were resistant to CH‐11 Ab, although they remained sensitive to VP‐16 or staurosporin. In the presence of cycloheximide, the selected SCCHN sublines become susceptible to CH‐11 Ab, and showed cleavage of caspase‐8, suggesting that apoptosis resistance was mediated by an inhibitory protein(s) acting upstream of caspase‐8. Overexpression of Fas‐associated phosphatase 1 (FAP‐1), but not cellular FLICE‐inhibitory protein (cFLIP) in SCCHN sublines was documented by Western blots and RT‐PCR analyses. The FAP‐1^+^ selected sublines also downregulated cell surface Fas. A high phosphorylation level of IκBκ, NFκB activation and upregulation of Bcl‐2 expression were observed in the FAP‐1^+^ sublines. Treatment with the phosphatase inhibitor, orthovanadate, or silencing of FAP‐1 with siRNA abolished their resistance to apoptosis, suggesting that FAP‐1 phosphatase activity could be responsible for NF‐κB activation and resistance of SCCHN cells to Fas‐mediated apoptosis. J. Cell. Biochem. 100: 16–28, 2007. © 2006 Wiley‐Liss, Inc.