Role of p38 MAPK in the cytokine reprogramming of a human leukemic cell line with a drug-resistant phenotype

Tumor cells have the capacity to develop coordinated resistance mechanisms that promote their survival and progression through the acquisition of multidrug resistance (MDR). This phenotype is the consequence of global cellular changes caused by antineoplastic drugs and may include modifications in the secretome, which influence the antitumoral immune response and the fate of resistant cells. In this study, we determined the cytokine secretion profile of human leukemic cells sensitive and resistant to several antineoplastic drugs. We also analyzed the p38 MAPK signaling pathway and its involvement in the regulation of both cytokine production and resistance. For this purpose, we generated a human leukemic model that consists of pre-B parental leukemic cells and their derived sublines resistant to several drugs (daunomycin, DNM; cisplatin, CDDP; methotrexate, MTX); an additional transfected subline with inducible expression of P-glycoprotein (P-gp) was obtained. We observed drastic differences in the cytokine secretion profiles of parental and P-gp-transfected cells and resistant sublines. Thus, whereas sensitive and transfected cells exhibit a cytokine regulatory profile, drug-resistant cells are characterized by a predominant inflammatory pattern that is similar in the three drug-resistant sublines, regardless of the drug that has induced the resistant phenotype. In parallel, we observed changes in the p38 MAPK activation profile in DNM-resistant versus DNM-sensitive cells after incubation under stress conditions (DNM at 0.1 µM or hypothermia). Furthermore, the use of a p38 MAPK pharmacological inhibitor decreases not only the IC50 value in DNM-resistant cells but also the cytokine secretion levels in parental and DNM-resistant cells, demonstrating that p38 signaling is a link between resistance and cytokine production in human leukemic cells. Together, our results suggest that cytotoxic drug-based treatments can modify the cytokine secretory pattern of pre-B leukemic cells, leading to a resistant phenotype through a mechanism that involves p38 MAPK activation. Defining the specific cytokine signatures and associated signaling circuits could provide valuable prognostic markers and aid in optimizing treatment strategies for refractory and/or relapsed patients.