Salinomycin induced ROS results in abortive autophagy and leads to regulated necrosis in glioblastoma

// Enric Xipell 1, 2, 3 , Marisol Gonzalez-Huarriz 1, 2, 3 , Juan Jose Martinez de Irujo 4 , Antonia García-Garzón 4 , Fred F. Lang 5 , Hong Jiang 5 , Juan Fueyo 5 , Candelaria Gomez-Manzano 5 , Marta M. Alonso 1, 2, 3 1 The Health Research Institute of Navarra (IDISNA), Pamplona, Spain 2 Program in Solid Tumors and Biomarkers, Foundation for the Applied Medical Research, Pamplona, Spain 3 Department of Pediatrics, University Hospital of Navarra, Pamplona, Spain 4 Department of Biochemistry University of Navarra, Pamplona, Spain 5 Brain Tumor Center, UT MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Marta M. Alonso, email: mmalonso@unav.es Keywords: glioblastoma, autophagy, regulated necrosis, ROS production Received: February 26, 2016      Accepted: April 02, 2016      Published: April 21, 2016 ABSTRACT Glioblastoma is the most frequent malignant brain tumor. Even with aggressive treatment, prognosis for patients is poor. One characteristic of glioblastoma cells is its intrinsic resistance to apoptosis. Therefore, drugs that induce alternative cell deaths could be interesting to evaluate as alternative therapeutic candidates for glioblastoma. Salinomycin (SLM) was identified through a chemical screening as a promising anticancer drug, but its mechanism of cell death remains unclear. In the present work we set out to elucidate how SLM causes cell death in glioblastoma cell lines (both established cell lines and brain tumor stem cell lines), aiming to find a potential antitumor candidate. In addition, we sought to determine the mechanism of action of SLM so that this mechanism can be can be exploited in the fight against cancer. Our data showed that SLM induces a potent endoplasmic reticulum (ER) stress followed by the trigger of the unfolded protein response (UPR) and an aberrant autophagic flux that culminated in necrosis due to mitochondria and lysosomal alterations. Of importance, the aberrant autophagic flux was orchestrated by the production of Reactive Oxygen Species (ROS). Alleviation of ROS production restored the autophagic flux. Altogether our data suggest that in our system the oxidative stress blocks the autophagic flux through lipid oxidation. Importantly, oxidative stress could be instructing the type of cell death in SLM-treated cells, suggesting that cell death modality is a dynamic concept which depends on the cellular stresses and the cellular mechanism activated.