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Farnesyltransferase Inhibitor SCH66336 Induces Rapid Phosphorylation of Eukaryotic Translation Elongation Factor 2 in Head and Neck Squamous Cell Carcinoma Cells

¹ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center; ² Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas; ³ Department of Otolaryngology, National Yang Ming University, Taipei Veteran General Hospital, Taipei, Taiwan; and ⁴ Department of Oncology/Hematology, Winship Cancer Institute, Emory University, Atlanta, Georgia

Request for reprints: Li Mao, Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-796-8655; E-mail: lmao{at}mdanderson.org.

Farnesyltransferase inhibitors (FTI) are a class of therapeutic agents designed to target tumors with mutations of the ras oncogene. However, the biological effect of FTIs is often independent of ras mutation status, which suggests the existence of additional mechanisms. In this study, we investigated the molecular effects of SCH66336 an FTI, in head and neck squamous cell carcinoma cells using proteomic approaches. We showed that SCH66336induced phosphorylation (inactivation) of eukaryotic translation elongation factor 2 (eEF2), an important molecule for protein synthesis, as early as 3 hours after SCH66336administration. Protein synthesis was subsequently reduced in the cells. Paradoxically, activation of eEF2 kinase (eEF2K), the only known kinase that regulates eEF2, was observed only at 12 hours after SCH66336treatment. Consistent with this observation, the inhibition of phosphorylated-MEK and phosphorylated-p70S6K, the two key signaling molecules responsible for activation of eEF2K, also occurred at least 12 hours after SCH66336administration. Our data suggest that inhibition of protein synthesis through inactivation of eEF2 is a novel mechanism of SCH66336mediated growth inhibition and that this effect is independent of ras-MEK/p70S6K-eEF2K signaling cascades.

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