Differential effects of N-TiO₂ nanoparticle and its photo-activated form on autophagy and necroptosis in human melanoma A375 cells

The manipulation of autophagy provides a new opportunity for highly effective anticancer therapies. Recently, we showed that photodynamic therapy (PDT) with nitrogen-doped titanium dioxide (N-TiO₂) nanoparticles (NPs) could promote the reactive oxygen species (ROS)-dependent autophagy in leukemia cells. However, the differential autophagic effects of N-TiO₂ NPs in the dark and light conditions and the potential of N-TiO_2-based PDT for the treatment of melanoma cells remain unknown. Here we show that depending on the visible-light condition, the autophagic response of human melanoma A375 cells to N-TiO₂ NPs switches between two different statuses (ie., flux or blockade) with the opposite outcomes (ie., survival or death). Mechanistically, low doses of N-TiO₂ NPs (1-100 µg/ml) stimulate a nontoxic autophagy flux response in A375 cells, whereas their photo-activation leads to the impairment of the autophagosome-lysosome fusion, the blockade of autophagy flux and consequently the induction of RIPK1-mediated necroptosis via ROS production. These results confirm that photo-controllable autophagic effects of N-TiO₂ NPs can be utilized for the treatment of cancer, particularly melanoma.