Autophagy in Osteosarcoma Cancer Stem Cells Is a Critical Process which Can Be Targeted by the Antipsychotic Drug Thioridazine

SIMPLE SUMMARY: Cancer stem cells (CSCs) represent a minor population of cancer cells with stem cell-like properties and appear as a crucial target in oncology as they are the origin of relapses and resistance to current treatments. Autophagy, which allows the degradation and recycling of cellular components for survival purposes, has been shown to be upregulated in some CSCs, participating in the resistance of these cells. The aim of our study was to analyze the autophagy level and the consequences of targeting this process in osteosarcoma CSCs. Our results indicate that autophagy is a critical process in osteosarcoma CSCs and that targeting this pathway allows to switch their fate from survival to death. ABSTRACT: Cancer stem cells (CSCs) represent a minor population of cancer cells with stem cell-like properties which are able to fuel tumor growth and resist conventional treatments. Autophagy has been described to be upregulated in some CSCs and to play a crucial role by maintaining stem features and promoting resistance to both hostile microenvironments and treatments. Osteosarcoma (OS) is an aggressive bone cancer which mainly affects children and adolescents and autophagy in OS CSCs has been poorly studied. However, this is a very interesting case because autophagy is often deregulated in this cancer. In the present work, we used two OS cell lines showing different autophagy capacities to isolate CSC-enriched populations and to analyze the autophagy in basal and nutrient-deprived conditions. Our results indicate that autophagy is more efficient in CSCs populations compared to the parental cell lines, suggesting that autophagy is a critical process in OS CSCs. We also showed that the antipsychotic drug thioridazine is able to stimulate, and then impair autophagy in both CSC-enriched populations, leading to autosis, a cell death mediated by the Na+/K(+) ATPase pump and triggered by dysregulated accumulation of autophagosomes. Taken together, our results indicate that autophagy is very active in OS CSCs and that targeting this pathway to switch their fate from survival to death could provide a novel strategy to eradicate these cells in osteosarcoma.