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

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 þ selected sublines also downregulated cell surface Fas. A high phosphorylation level of IkBk, NFkB activation and upregulation of Bcl-2 expression were observed in the FAP-1 þ 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-kB activation and resistance of SCCHN cells to Fas-mediated apoptosis.

Molecular basis of parthenolide-dependent proapoptotic activity in cancer cells.

“…All these genetic events lead to increased NF-κB transcriptional activity, thus indicating that NF-κB target genes might control important steps for cellular transformation or cancer progression. It was reported that NF-κB may control not only apoptosis and cell cycle progression, but also invasion and metastasis [22,23]. 3.…”

PTPL1: a large phosphatase with a split personality

“…PTPL1 expression was reported to inhibit Fas-mediated apoptosis in both pancreatic adenocarcinoma [45,46] and melanoma [47] cell lines thus acting as a survival mechanism in tumor cells expressing both Fas and FasL. Additional tumor models of ovarian cancer [48], colon cancer [49], head/ neck cancer [50], hepatocellular carcinoma [51], and hepatoblastoma [52] also showed a correlation between tumor cell survival in the presence of both Fas/FasL and expression of PTPL1. While some functional and correlative evidence exists for the regulation of Fas by PTPL1, at least one potential mechanism is explored below.…”

Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

“…FAP-1 overexpression has been reported to inhibit Fas-mediated apoptosis in certain human malignant cells, by acting as a negative switch in the Fas/FasL pathway, thereby providing them with a marked survival advantage (32,33). Moreover, silencing of FAP-1 gene expression or inhibition of FAP-1 protein tyrosine phosphatase (PTP) activity could abolish tumor cell resistance to Fas-induced apoptosis in a head and neck cancer model system (SCCHN cells) (105). In contrast, FADD protein, another critical component that positively regulates the Fas/FasL apoptotic potency (intermediates between the activated Fas and immature Caspase-8) (12,26,33), might not essentially contribute to cisplatin-induced apoptosis of RT4 and T24 cells, since the corresponding FADD gene activities in response to the drug remained unaffected in both cell types examined (data not shown).…”