title: Proteasome inhibitor sensitizes oral squamous cell carcinoma cells to TRAIL-mediated apoptosis.
abstract: Oral squamous cell carcinoma (OSCC) cells are relatively resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis during culture. We investigated the role of a proteaosome inhibitor in the survival and apoptosis of these cells. We found that the proteasome inhibitor MG132 markedly accelerated TRAIL-mediated apoptosis in OSCC cell lines HSC-2 and HSC-3. Addition of TRAIL to MG132-treated cells resulted in Bid cleavage. Furthermore, the inhibitors of caspase-3, caspase-8 and caspase-9 reduced the accelerative effect of MG132 on TRAIL-mediated apoptosis. These results suggest that the pro-apoptotic effect of a proteasome inhibitor on TRAIL-mediated apoptosis may contribute to both extrinsic and intrinsic pathways. MG132 enhanced the expression of the TRAIL receptors DR4 and DR5, and neutralization of DR5 receptors showed a marked reduction of TRAIL-mediated apoptosis, whereas that of DR4 was a partial reduction. MG132 also markedly reduced cellular FLICE-inhibitory protein (c-FLIP), cellular inhibitor of apoptosis protein-1 (cIAP-1), X-linked IAP (XIAP) and survivin. Therefore, MG132 provides partial regulation of TRAIL-mediated apoptosis in OSCC cells via modulation of DR5, c-FLIP, cIAP-1, XIAP and survivin. The proteasome inhibitor MG132 may therefore represent a novel strategy for overcoming resistance to TRAIL-mediated apoptosis in OSCC cells.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, 2-1-1 Kitasenzoku, Ota-ku, Tokyo 145-8515, Japan. yoshiba@dent.showa-u.ac.jp
authors.forename: Sayaka
authors.initials: S
authors.lastname: Yoshiba
authors.forename: Masayasu
authors.initials: M
authors.lastname: Iwase
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kurihara
authors.forename: Makiko
authors.initials: M
authors.lastname: Uchida
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kurihara
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Satoru
authors.initials: S
authors.lastname: Shintani
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D007976:Leupeptins / Q000008:administration & dosage / Q000494:pharmacology*; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D061988:Proteasome Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde