Farnesyltransferase inhibitor SCH66336 induces rapid phosphorylation of eukaryotic translation elongation factor 2 in head and neck squamous cell carcinoma cells.
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 SCH66336 induced phosphorylation (inactivation) of eukaryotic translation elongation factor 2 (eEF2), an important molecule for protein synthesis, as early as 3 hours after SCH66336 administration. 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 SCH66336 treatment. 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 SCH66336 administration. Our data suggest that inhibition of protein synthesis through inactivation of eEF2 is a novel mechanism of SCH66336-mediated growth inhibition and that this effect is independent of ras-MEK/p70S6K-eEF2K signaling cascades.
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Hening
H
Ren
Shyh-Kuan
SK
Tai
Fadlo
F
Khuri
Zuming
Z
Chu
Li
L
Mao
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000595:Amino Acid Sequence; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D051231:Farnesyltranstransferase; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis; D020652:Peptide Elongation Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D009363:Neoplasm Proteins; D020652:Peptide Elongation Factor 2; D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes