Autophagy and oxidative stress modulation mediate Bortezomib resistance in prostate cancer.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Multiple Myeloma*/drug therapy ; Hematologic Neoplasms*/pathology ; Prostatic Neoplasms*/drug therapy ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/therapeutic use; Humans ; Adult ; Male ; Bortezomib/pharmacology ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors/pharmacology ; Proteasome Inhibitors/therapeutic use ; Oxidative Stress ; Autophagy ; Ubiquitins/metabolism

Proteasome 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 to impairment of the proteasome-ubiquitin system. However, a major problem limiting their efficacy is the emergence of resistance. Their application to 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 highlight the role of autophagy and oxidative stress regulation in Bortezomib resistance and elucidate key proteins of signaling pathways as potential pharmaceutical targets, which could increase the efficiency of proteasome-targeting therapies, thus expanding the group of molecular targets for neoplastic disorders.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Zafeiropoulou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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69G8BD63PP (Bortezomib)
EC 3.4.25.1 (Proteasome Endopeptidase Complex)
0 (Proteasome Inhibitors)
0 (Ubiquitins)
0 (Antineoplastic Agents)

Date Created: 20240227 Date Completed: 20240229 Latest Revision: 20240229

20240229

PMC10898778

10.1371/journal.pone.0289904

38412186