Activation of the integrated stress response regulates lovastatin-induced apoptosis

Lovastatin, a potent inhibitor of mevalonate synthesis, can readily induce apoptosis in a subset of human tumor types including head and neck squamous cell carcinomas (HNSCC). We recently identified activation of transcription factor (ATF) 4 as a lovastatin induced gene in HNSCC cells. ATF4 plays a significant role in regulating cellular responses to a wide variety of stress inducers known as the integrated stress response (ISR). These cell stresses lead to the phosphorylation of eukaryotic initiation factor (eIF) 2 alpha shutting down global protein translation. However, the translation of ATF4 is enhanced. In this study, lovastatin treatment induced eIF2 alpha phosphorylation and inhibited global protein translation. ATF4 expression was induced followed by increased ATF3 andCHOPexpression, targets of ATF4 activity, in SCC25 HNSCC cells. In CHOP (-)/(-) murine embryonic fibroblasts (MEFs), lovastatin- induced apoptosis was attenuated indicating a role for CHOP in this response. Furthermore, the eIF2 alpha kinase GCN2 mediates lovastatin induction of ATF4 and lovastatin- induced apoptosis was also attenuated in GCN2 (-)/(-) MEFs. The pro- drug version of lovastatin has potential proteasome inhibitory activity and recently a variety of well established proteasome inhibitors were shown to activate the ISR. In this study, neither the pro- drug nor the active forms of lovastatin had any significant effect on proteasome activity. Therefore, lovastatin, by targeting mevalonate synthesis, is a potent inducer of the ISR through a novel and as yet unrecognized mechanism.