Enhancement of susceptibility to Fas-mediated apoptosis in oral squamous cell carcinoma cells by phosphatidylinositol 3-kinase inhibitor.
In general, oral squamous cell carcinoma (OSCC) cells are relatively resistant to Fas-mediated apoptosis during in vitro culture. Here, we studied the role of survival/apoptosis associated phosphatidylinositol 3-kinase (PI 3-K)/Akt in this process. We found that both PI 3-K inhibitors, wortmannin and LY294002, markedly suppressed the phosphorylation of Akt and accelerated Fas-mediated apoptosis in OSCC cells. It was found that caspase-3 and -8 inhibitors reduced the accelerative effect of PI 3-K inhibitor on Fas-mediated apoptosis in OSCC cells, but not caspase-9 inhibitor. Although PI 3-K inhibitors did not affect the Fas expression of OSCC cells, cellular FLICE-inhibitory protein (c-FLIP) levels were markedly reduced by PI 3-K inhibitor treatment. Moreover, antisense oligonucleotide to c-FLIP confirmed that the down-regulation of c-FLIP enhanced the sensitization to Fas-mediated apoptosis in OSCC cells. These results suggest that PI 3-K/Akt signaling pathway may, in part, regulate Fas-mediated apoptosis in OSCC cells through c-FLIP expression.
Kondo
Gen
G
Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, 2-1-1, Kitasenzoku, Ota-ku, Tokyo 145-8515, Japan.
Iwase
Masayasu
M
Watanabe
Hitoshi
H
Uchida
Makiko
M
Takaoka
Sayaka
S
Ohashi
Masaru
M
Nagumo
Masao
M
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000077191:Wortmannin; D019014:fas Receptor / Q000378:metabolism*
D000730:Androstadienes; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019014:fas Receptor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051058:Oncogene Protein v-akt; D000077191:Wortmannin