8772

FADD

Fas (TNFRSF6)-associated via death domain;FADD;Fas (TNFRSF6)-associated via death domain

FAS-associated death domain protein|Fas-associating death domain-containing protein|Fas-associating protein with death domain|growth-inhibiting gene 3 protein|mediator of receptor induced toxicity|mediator of receptor-induced toxicity

11q13.3

protein-coding

Anti-oestrogen therapy is effective for control of hormone receptor-positive breast cancers, although the detailed molecular mechanisms, including signal transduction, remain unclear. We demonstrated here that long-term tamoxifen treatment causes G2/M cell cycle arrest through c-jun N-terminal kinase (JNK) activation, which is dependent on phosphorylation of Fas-associated death domain-containing protein (FADD) at 194 serine in an oestrogen (ER) receptor-positive breast cancer cell line, MCF-7. expression of a dominant negative mutant form of MKK7, a kinase upstream of JNK, or mutant FADD (S194A) in MCF-7 cells suppressed the cytotoxicity of long-term tamoxifen treatment. Of great interest, similar signallings could be evoked by paclitaxel, even in an ER-negative cell line, MDA-MB-231. In addition, immunohistochemical analysis using human breast cancer specimens showed a close correlation between phosphorylated JNK and FADD expression, both being significantly reduced in cases with metastatic potential. We conclude that JNK-mediated phosphorylation of FADD plays an important role in the negative regulation of cell growth and metastasis, independent of the ER status of a breast cancer, so that JNK/FADD signals might be promising targets for cancer therapy.

Many types of cancer cells are resistant to Fas-mediated apoptosis by several mechanisms, including the mutations of the genes involved in Fas-mediated apoptosis. In this study, to explore the possibility that the mutations of the genes involved in the proximal pathway of Fas-mediated apoptosis (Fas, FADD, caspase 8 and caspase 10) are involved in cancer metastasis, we have analysed somatic mutation and deletion of these genes in 80 non-small cell lung cancers (NSCLCs) with (n=43) and without (n=37) metastasis to the regional lymph nodes. We found 12 mutations (four Fas, four FADD, and four caspase 10 mutations) in 11 of 80 NSCLCs (13.8%). Interestingly, of these mutations, most mutations (10 out of 12) were detected in the NSCLCs with metastasis, and the frequency in the metastasis lesions (23%) was higher than that in the primary lesions of the NSCLCs without metastasis (5.4%). Furthermore, transfection study revealed that the tumor-derived mutants have decreased apoptosis inductions compared to the wild types. These data suggest that the inactivating mutations of the genes in the proximal pathway of Fas-mediated apoptosis may lead to a decreased cancer cell death and play a role in the metastasis of NSCLC.

BACKGROUND: The Fas-associated death domain-containing protein, FADD, is an adaptor for relaying apoptotic signals. However, recent studies have shown that FADD also plays an important role in the growth and regulation of the cell cycle. The purpose of this study was to elucidate the role of FADD in oral squamous cell carcinoma (SCC). METHODS: The DNA amplification of FADD from 30 samples of tongue SCC was analyzed using real-time PCR and the protein expression of FADD from 60 samples of tongue SCC was analyzed using immunohistochemistry. RESULTS: The DNA amplifications of FADD were observed in 13 cases (44.3%) and were significantly correlated with the histopathological differentiation grade of SCCs (P = 0.009). FADD expression levels compared with the matched adjacent epithelium increased significantly (P = 0.000). Additionally, the positive expressions of FADD were significantly correlated with lymph node metastasis of SCCs (P = 0.029) and the 5-year disease-specific survival rates (P = 0.049). A positive association between FADD expression level and the histopathological differentiation grade was found to be limited to T1 SCCs (P = 0.019). DNA amplification was moderately correlated (correlation coefficient = 0.406, P = 0.026) with expression of FADD in 30 samples of tongue SCC. CONCLUSION: In tongue SCCs, the expression of FADD was higher when compared with that of adjacent areas, which might be determined via genomic amplification in 11q13.3. Thus, SCC cells with the expression of FADD are possibly more likely to become metastatic and to worsen survival rates.