title: Inhibition of mTOR/eIF4E by anti-viral drug ribavirin effectively enhances the effects of paclitaxel in oral tongue squamous cell carcinoma.
abstract: Upregulation of eIF4E is associated with poor clinical outcome in many human cancers and represents a potential therapeutic target. However, the function of eIF4E remains unknown in oral tongue squamous cell carcinoma (OTSCC). In this work, we show that ribavirin, an anti-viral drug, effectively augments sensitivity of OTSCC cells to paclitaxel via inhibiting mTOR/eIF4E signaling pathway. Ribavirin dose-dependently inhibits proliferation and induces apoptosis in SCC-9 and CAL27 cells. Combination of ribavirin and paclitaxel are more effective in inhibiting proliferation and inducing apoptosis in OTSCC cells. Importantly, the in vivo efficacy of ribavirin and its synergism with paclitaxel is confirmed by two independent OTSCC xenograft mouse models. Mechanistically, ribavirin significantly decreases mTOR/eIF4E signaling pathway in OTSCC cells via suppressing phosphorylation of Akt, mTOR, 4EBP1 and eIF4E. Overexpression of the phosphor-mimetic form of eIF4E (eIF4E S209D) but not the nonphosphorylatable form (eIF4E S209A) reverses the effects of ribavirin, confirming that eIF4E inhibition is the mechanism of action of ribavirin in OTSCC cells. In addition, eIF4E depletion significantly enhances the anti-proliferative and pro-apoptotic effects of paclitaxel, demonstrating the critical role of eIF4E in OTSCC cell response to paclitaxel. Our work is the first to demonstrate the efficacy of ribavirin as a single agent and synergism as combination with paclitaxel in OTSCC in vitro and in vivo. Our findings also demonstrate the therapeutic value of inhibiting eIF4E in OTSCC treatment.
authors.affiliation: Department of Stomatology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, People's Republic of China.
authors.forename: Dehua
authors.initials: D
authors.lastname: Dai
authors.affiliation: Department of Stomatology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, People's Republic of China.
authors.forename: Hujie
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Stomatology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Stomatology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, People's Republic of China. Electronic address: 365443309@qq.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000737:chemistry; D000998:Antiviral Agents / Q000737:chemistry; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D029543:Nucleocytoplasmic Transport Proteins / Q000037:antagonists & inhibitors*; D017239:Paclitaxel / Q000737:chemistry*; D012254:Ribavirin / Q000737:chemistry*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014062:Tongue Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D000998:Antiviral Agents; C411571:EIF4ENIF1 protein, human; D029543:Nucleocytoplasmic Transport Proteins; D012254:Ribavirin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel
keywords: Drug repurposing; Ribavirin; Tongue squamous carcinoma; eIF4E