Enhancement of susceptibility to Fas-mediated apoptosis in oral squamous cell carcinoma cells by phosphatidylinositol 3-kinase inhibitor

• Published in: Oral oncology Vol. 42; no. 7; pp. 745 - 752
• Main Authors: Kondo, Gen, Iwase, Masayasu, Watanabe, Hitoshi, Uchida, Makiko, Takaoka, Sayaka, Ohashi, Masaru, Nagumo, Masao
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.08.2006; Elsevier
• Subjects: Androstadienes - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; c-FLIP; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; Chromones - pharmacology; Down-Regulation; Enzyme Inhibitors - pharmacology; Fas; fas Receptor - metabolism; Flow Cytometry; Humans; Medical sciences; Morpholines - pharmacology; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; Oncogene Protein v-akt - metabolism; Otorhinolaryngology. Stomatology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphorylation; PI 3-K; Signal Transduction - drug effects; Squamous cell carcinoma; Tumor Cells, Cultured; Tumors; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology; Fas; Squamous cell carcinoma; c-FLIP; PI 3-K; Apoptosis; Enzyme; Stomatology; Transferases; ENT; Malignant tumor; Oral squamous cell carcinoma; 1-Phosphatidylinositol 3-kinase; Sensitivity; Cancerology; Squamous cell carcinoma Fas; Oral cavity disease; Cell
• ISSN: 1368-8375; 1879-0593
• DOI: 10.1016/j.oraloncology.2005.11.015

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.