Enhanced susceptibility of oral squamous cell carcinoma cell lines to FAS-mediated apoptosis by cisplatin and 5-fluorouracil.
Our study was conducted to investigate whether anticancer drugs, cisplatin (CDDP) and/or 5-fluorouracil (5-FU), can modulate Fas-mediated apoptosis in oral squamous cell carcinoma (OSCC) cell lines. When OSCC cell lines, NA and HSC-4, were treated with CDDP and/or 5-FU, Fas and its mRNA expression on the plasma membrane were enhanced. An increase in caspase-3 and -8 activities was then observed by the addition of agonistic anti-Fas antibody, CH-11. Apoptosis of OSCC cells treated with anticancer drugs were significantly enhanced by CH-11, whereas untreated cells were nearly resistant to apoptosis. Moreover, the combination of CDDP and 5-FU resulted in an increasing susceptibility to apoptosis. Caspase-3 and -8 inhibitors, but not caspase-9 inhibitor, reduced Fas-mediated apoptosis enhanced by the anticancer drugs. Furthermore, OSCC cells treated with anticancer drugs exhibited decreased cellular FADD-like interleukin 1-converting enzyme-inhibitory protein (c-FLIP) levels, whereas neither the Fas-associated death domain-containing protein (FADD) nor procaspase-8 changed the expression. Moreover, antisense oligonucleotide to c-FLIP confirmed that down-regulation of c-FLIP induced sensitization to Fas-mediated apoptosis. These results suggest that CDDP and 5-FU may enhance the susceptibility to Fas-mediated apoptosis through down-regulation of c-FLIP. From these findings, a new potential strategy may be developed to improve the efficacy of anticancer drugs.
Iwase
Masayasu
M
Second Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo, Japan.
Watanabe
Hitoshi
H
Second Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo, Japan.
Kondo
Gen
G
Second Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo, Japan.
Ohashi
Masaru
M
Second Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo, Japan.
Nagumo
Masao
M
Second Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo, Japan.
D017304:Annexin A5 / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D029681:Arabidopsis Proteins; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000378:metabolism; D044943:Fatty Acid Desaturases / Q000378:metabolism; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism*
D017304:Annexin A5; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D029681:Arabidopsis Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D017931:DNA Primers; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019014:fas Receptor; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; D020169:Caspases; D002945:Cisplatin; D005472:Fluorouracil