Ubash3b promotes TPA-mediated suppression of leukemogenesis through accelerated downregulation of PKCδ protein.

Autor: Yao Y; State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, 550014, PR China., Liu W; State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, 550014, PR China., Gajendran B; State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, 550014, PR China., Wang C; State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, 550014, PR China., Zacksenhaus E; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada., Sample KM; The National Health Commission's Key Laboratory of Immunological Pulmonary Disease, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou University, Guiyang, Guizhou, 550002, PR China., Varier KM; State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, 550014, PR China., Hao X; State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, 550014, PR China., Ben-David Y; State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, 550014, PR China. Electronic address: yaacovbendavid@hotmail.com.
Jazyk: angličtina
Zdroj: Biochimie [Biochimie] 2021 May; Vol. 184, pp. 8-17. Date of Electronic Publication: 2021 Feb 05.
DOI: 10.1016/j.biochi.2021.02.001
Abstrakt: Acquired drug-resistance, often involving downregulation or mutations in the target protein, is a major caveat in precision medicine. Understanding mechanisms of resistance to therapeutic drugs may unravel strategies to overcome or prevent them. We previously identified phorbol ester (PE) compounds such as TPA that induce Protein Kinase δ (PKCδ), thereby suppressing leukemogenesis. Here we identified erythroleukemia cell lines that resist PEs and showed that reduced PKCδ protein expression underlies drug resistance. Reduced level of PKCδ in resistant cell lines was due to its phosphorylation followed by protein degradation. Indeed, proteasome inhibition prevented PE-induced loss of PKCδ. Accordingly, a combination of TPA and the proteasome inhibitor ALLN significantly suppressed leukemia in a mouse model of leukemia. PKCδ downregulation by TPA was independent of the downstream MAPK/ERK/P38/JNK pathway. Instead, expression of ubiquitin-associated and SH3 domain-containing protein b (Ubash3b) was induced by TPA, which leads to PKCδ protein dephosphorylation and degradation. This specific degradation was blocked by RNAi-mediated depletion of Ubash3b. In drug-sensitive leukemic cells, TPA did not induce Ubash3b, and consequently, PKCδ levels remained high. A PE-resistant cell line derived from PE-treated sensitive cells exhibited very low PKCδ expression. In these drug resistance cells, a Ubash3b independent mechanism led to PKCδ degradation. Thus, PE compounds in combination with proteasome or specific inhibitors for Ubash3b, or other factors can overcome resistance to TPA, leading to durable suppression of leukemic growth. These results identify Ubash3b as a potential target for drug development.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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