title: Farnesyltransferase inhibitor attenuates methamphetamine toxicity-induced Ras proteins activation and cell death in neuroblastoma SH-SY5Y cells.
abstract: Several lines of evidence support that methamphetamine (METH) toxicity plays a pivotal role in neurodegenerative diseases. However, the molecular mechanisms underlying METH-induced neurotoxicity are still unclear. In addition, Ras modulated death signaling has been continually reported in several cell types. In this study, intracellular Ras-dependent death signaling cascade activation was proposed to contribute to METH-induced neuronal cell degeneration in dopaminergic SH-SY5Y cultured cells. Exposure to a toxic dose of METH significantly decreased cell viability, and tyrosine hydroxylase phosphorylation, but increased c-Jun phosphorylation and active, GTP-bound Ras in cultured SH-SY5Y cells. Farnesyltransferase inhibitor, FTI-277, an inhibitor of the enzyme catalyzed the farnesylation of Ras proteins was able to diminish the toxic effects of METH on induction in cell degeneration, activation in c-Jun-N-terminal kinase cascades, and Ras activation in SH-SY5Y cells. The results of this study show that activation in Ras signaling cascade may be implicated in the METH-induced death signaling pathway in neuroblastoma SH-SY5Y cells.
authors: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhonpathom, Thailand.
authors: Nipawan
authors: N
authors: Pirompul
authors: Piyarat
authors: P
authors: Govitrapong
authors: Banthit
authors: B
authors: Chetsawang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008694:Methamphetamine / Q000633:toxicity*; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C096856:FTI 277; D008694:Methamphetamine; D008715:Methionine; D051231:Farnesyltranstransferase; D018631:ras Proteins