Dexamethasone-Induced Fatty Acid Oxidation and Autophagy/Mitophagy Are Essential for T-ALL Glucocorticoid Resistance

Simple Summary Reduced response to glucocorticoids (GCs, such as dexamethasone, Dex), first-line drugs employed during therapy induction, is considered a poor prognosis factor for T-cell acute lymphoblastic leukemia (T-ALL) patients. Here, the effects of Dex in patient-derived T-ALL cell lines were analyzed. Dex primarily targeted and rapidly accumulated in mitochondria, eventually causing a metabolic switch from glycolysis and glutaminolysis towards lipolysis and increased fatty acid oxidation (FAO), mitochondrial extra energization, and increased ROS production. Finally, mitochondrial damage/fission and autophagy/mitophagy were observed. Prevention of either FAO or autophagy greatly sensitized both T-ALL cells to Dex, which can be used to overcome GC resistance in T-ALL. ALL is a highly aggressive subtype of leukemia that affects children and adults. Glucocorticoids (GCs) are a critical component of the chemotherapeutic strategy against T-ALL. Cases of resistance to GC therapy and recurrent disease require novel strategies to overcome them. The present study analyzed the effects of Dex, one of the main GCs used in ALL treatment, on two T-ALL cell lines: resistant Jurkat and unselected CCRF-CEM, representing a mixture of sensitive and resistant clones. In addition to nuclear targeting, we observed a massive accumulation of Dex in mitochondria. Dex-treated leukemic cells suffered metabolic reprogramming from glycolysis and glutaminolysis towards lipolysis and increased FAO, along with increased membrane polarization and ROS production. Dex provoked mitochondrial fragmentation and induced autophagy/mitophagy. Mitophagy preceded cell death in susceptible populations of CCRF-CEM cells while serving as a pro-survival mechanism in resistant Jurkat. Accordingly, preventing FAO or autophagy greatly increased the Dex cytotoxicity and overcame GC resistance. Dex acted synergistically with mitochondria-targeted drugs, curcumin, and cannabidiol. Collectively, our data suggest that GCs treatment should not be neglected even in apparently GC-resistant clinical cases. Co-administration of drugs targeting mitochondria, FAO, or autophagy can help to overcome GC resistance.