Abstract
AbstractProteasome inhibitors such as Bortezomib, represent an established type of targeted treatment for several types of hematological malignancies, including multiple myeloma, Waldenstrom’s macroglobulinemia and mantle cell lymphoma, based on the cancer cell’s susceptibility upon impairment of the proteasome-ubiquitin system. However, a major problem limiting their efficacy is the emergence of resistance. Their application on solid tumors is currently being studied, while simultaneously, a wide spectrum of hematological cancers, such as Myelodysplastic Syndromes show minimal or no response to Bortezomib treatment. In this study, we utilize the prostate cancer cell line DU-145 to establish a model of Bortezomib resistance, studying the underlying mechanisms. Evaluating the resulting resistant cell line, we observed restoration of proteasome chymotrypsin-like activity, regardless of drug presence, an induction of pro-survival pathways, and the substitution of the Ubiquitin-Proteasome System role in proteostasis by induction of autophagy. Finally, an estimation of the oxidative condition of the cells, indicated that the resistant clones reduce the generation of reactive oxygen species induced by Bortezomib, to levels even lower than those induced in non-resistant cells. Our findings elucidate key proteins of survival and stress regulation pathways as potential pharmaceutical targets, which could increase the efficiency of the proteasome-targeting therapies, thus expanding the group of molecular targets for neoplastic disorders.
Publisher
Cold Spring Harbor Laboratory
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