title: Aborted autophagy and nonapoptotic death induced by farnesyl transferase inhibitor and lovastatin.
abstract: Exposure of the human malignant peripheral nerve sheath tumor cell lines STS-26T, ST88-14, and NF90-8 to nanomolar concentrations of both lovastatin and farnesyl transferase inhibitor (FTI)-1 but not to either drug alone induced cell death. ST88-14 and NF90-8 cells underwent apoptosis, yet dying STS-26T cells did not. FTI-1 cotreatment induced a strong and sustained autophagic response as indicated by analyses of microtubule-associated protein-1 light chain 3 (LC3)-II accumulation in STS-26T cultures. Extensive colocalization of LC3-positive punctate spots was observed with both lysosome-associated membrane protein (LAMP)-1 and LAMP-2 (markers of late endosomes/lysosomes) in solvent or FTI-1 or lovastatin-treated STS-26T cultures but very little colocalization in lovastatin/FTI-1-cotreated cultures. The absence of colocalization in the cotreatment protocol correlated with loss of LAMP-2 expression. Autophagic flux studies indicated that lovastatin/FTI-1 cotreatment inhibited the completion of the autophagic program. In contrast, rapamycin induced an autophagic response that was associated with cytostasis but maintenance of viability. These studies indicate that cotreatment of STS-26T cells with lovastatin and FTI-1 induces an abortive autophagic program and nonapoptotic cell death.
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Wojtkowiak
authors.forename: Komal M
authors.initials: KM
authors.lastname: Sane
authors.forename: Miriam
authors.initials: M
authors.lastname: Kleinman
authors.forename: Bonnie F
authors.initials: BF
authors.lastname: Sloane
authors.forename: John J
authors.initials: JJ
authors.lastname: Reiners
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Mattingly
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008148:Lovastatin / Q000008:administration & dosage*; D051379:Mice; D051381:Rats
chemical_list: D004338:Drug Combinations; D004791:Enzyme Inhibitors; D008148:Lovastatin; D051231:Farnesyltranstransferase