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 the farnesyltransferase inhibitor FTI-1, but not 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 LC3-II accumulation in STS-26T cultures. Extensive colocalization of LC3 positive punctate spots was observed with both LAMP-1 and LAMP-2 (markers of late endosomes/lysosomes) in solvent, 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 non-apoptotic cell death.
- Farnesyl transferase inhibitors
- Malignant peripheral nerve sheath tumors
- Received August 31, 2010.
- Revision received January 10, 2011.
- Accepted January 11, 2011.
- The American Society for Pharmacology and Experimental Therapeutics