Influence of nonprotective autophagy and the autophagic switch on sensitivity to cisplatin in non-small cell lung cancer cells

Abstract

While therapy-induced autophagy is conventionally conceived to be cytoprotective in nature, previous studies have identified multiple functions of autophagy, including a nonprotective form, as well as the existence of a switch between the different forms of autophagy. The current work provides further evidence of an autophagic switch, in this case in response to the antitumor drug, cisplatin, in non-small cell lung cancer cells that are either wild-type (p53wt) or functionally null in p53 (crp53), the latter generated using CRISPR/Cas9 technology. Pharmacological and genetic inhibition of autophagy identified nonprotective autophagy in p53wt cells and cytoprotective autophagy in crp53 cells. Furthermore, differences in cisplatin sensitivity between the two cell lines proved to be largely a function of the nature of the autophagy. Specifically, autophagy inhibition in the crp53 cells converts the temporal profile for the loss of cell viability in response to cisplatin to essentially parallel that observed in the p53wt cells. This enhanced sensitivity is due to cisplatin-induced apoptosis that occurs without necessitating the restoration of functional p53. In contrast, inhibition of autophagy has no observable impact on the temporal response profile exhibited in response to cisplatin in the p53wt cells, or the extent of cisplatin-induced apoptosis in the p53wt cells, consistent with the functional definition of nonprotective autophagy. Taken together, our current studies provide evidence that nonprotective autophagy in p53wt non-small cell lung cancer cells can be "switched" to protective autophagy in isogenic crp53 cells, and furthermore that inhibition of cytoprotective autophagy is sufficient to restore cisplatin sensitivity in the crp53 cells, largely through the increased promotion of apoptosis, despite the absence of functional p53.

Keywords: Autophagic switch; Autophagy; Cisplatin; Drug resistance; Drug sensitivity; Lung cancer; P53; Therapy-induced autophagy.