RESUMEN
Acute lymphoblastic leukaemia (ALL) is the most frequent childhood cancer and, although it is highly treatable, resistance to therapy, toxicity and side effects remain challenging. The synthetic glucocorticoid (GC) dexamethasone (Dex) is commonly used to treat ALL, the main drawback of which is the development of resistance to this treatment. The aim of the present study was to investigate potential molecular circuits mediating resistance and sensitivity to GCinduced apoptosis in ALL. The leukaemia cell lines CEMC714, CEMC115 and MOLT4 treated with chloroquine (CLQ), thapsigargin (TG) and rotenone (ROT) were used to explore the roles of autophagy, endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and reactive oxygen species (ROS) generation in the response to GC treatment. ROS levels were associated with increased cell death and mitochondrial membrane potential in rotenonetreated CEM cells. Autophagy inhibition by CLQ exhibited the strongest cytotoxic effect in GCresistant leukaemia. Autophagy may act as a prosurvival mechanism in GCresistant leukaemia since increasing trends in beclin1 and microtubuleassociated protein 1 light chain 3α levels were detected in CEMC115 and MOLT4 cells treated with Dex, whereas decreasing trends in these autophagy markers were observed in CEMC714 cells. The intracellular protein levels of the ER stress markers glucoseregulated protein (GRP)78 and GRP94 were stimulated by Dex only in the GCsensitive cells, suggesting a role of these chaperones in the GCmediated ALL cell death. Increased cell surface levels of GRP94 were recorded in CEMC714 cells treated with combination of Dex with TG compared with those in cells treated with TG alone, whereas decreasing trends were observed in CEMC115 cells under these conditions. Taken together, the results of the present study demonstrated that autophagy may be a prosurvival mechanism in GCresistant leukaemia, and by modulating intracellular and surface GRP94 protein levels, Dex is involved in the regulation of ER stress/UPRdependent cell death and immune surveillance. These observations may be of clinical importance if confirmed in patients.