Coordinate autophagy and translation inhibition enhance cell death in melanoma.

Abstract

Melanoma treatments are necessary when surgically curable treatments are limited. The major challenge of targeted therapy for treating malignant melanoma is acquired drug resistance. Translation and autophagy pathways are interconnected and involved in developing cancer drug resistance. We hypothesized that coordinate inhibition of autophagy and translation would lead to a better anticancer effect. In the present study, we used chloroquine combined with two translation inhibitors (NVP-BEZ235 and CGP57380) acting at different signaling pathway levels, activating the translation. Our study was conducted for human melanoma cell lines with similar genomic alteration (BRAFV600E and PTEN loss). The combination of the drugs suppresses cell invasiveness and growth by inducing apoptosis. We showed multiple direct and indirect interactions, indicating the overlap and interaction between the translation machinery and autophagy. These data suggest that coordinated inhibition of translation and autophagy promotes apoptosis and may be a new therapeutic model for melanoma treatment.