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Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/β-Catenin Pathway

Multiple myeloma (MM) is a hematopoietic malignancy characterized by the clonal proliferation of antibody-secreting plasma cells. Bortezomib (BZM), the first FDA-approved proteasome inhibitor, has significant antimyeloma activity and prolongs the median survival of MM patients. However, MM remains i...

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Autores principales: Jin, Yulong, Xu, Li, Wu, Xiaodong, Feng, Juan, Shu, Mimi, Gu, Hongtao, Gao, Guangxun, Zhang, Jinyi, Dong, Baoxia, Chen, Xiequn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cognizant Communication Corporation 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848415/
https://www.ncbi.nlm.nih.gov/pubmed/30837032
http://dx.doi.org/10.3727/096504018X15443011011637
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author Jin, Yulong
Xu, Li
Wu, Xiaodong
Feng, Juan
Shu, Mimi
Gu, Hongtao
Gao, Guangxun
Zhang, Jinyi
Dong, Baoxia
Chen, Xiequn
author_facet Jin, Yulong
Xu, Li
Wu, Xiaodong
Feng, Juan
Shu, Mimi
Gu, Hongtao
Gao, Guangxun
Zhang, Jinyi
Dong, Baoxia
Chen, Xiequn
author_sort Jin, Yulong
collection PubMed
description Multiple myeloma (MM) is a hematopoietic malignancy characterized by the clonal proliferation of antibody-secreting plasma cells. Bortezomib (BZM), the first FDA-approved proteasome inhibitor, has significant antimyeloma activity and prolongs the median survival of MM patients. However, MM remains incurable predominantly due to acquired drug resistance and disease relapse. β-Catenin, a key effector protein in the canonical Wnt signaling pathway, has been implicated in regulating myeloma cell sensitivity to BZM. Decitabine (DAC) is an epigenetic modulating agent that induces tumor suppressor gene reexpression based on its gene-specific DNA hypomethylation. DAC has been implicated in modulating Wnt/β-catenin signaling by promoting the demethylation of the Wnt/β-catenin antagonists sFRP and DKK. In this study, we report the effects of single reagent DAC therapy and DAC combined with BZM on β-catenin accumulation, myeloma cell survival, apoptosis, and treatment sensitivity. Our study proved that DAC demethylated and induced the reexpression of the Wnt antagonists sFRP3 and DKK1. DAC also reduced GSK3β (Ser9) phosphorylation and decreased β-catenin accumulation in the nucleus, which were induced by BZM. Thus, the transcription of cyclin D1, c-Myc, and LEF/TCF was reduced, which synergistically inhibited cell proliferation, enhanced BZM-induced apoptosis, and promoted BZM-induced cell cycle arrest in myeloma cells. In summary, these results indicated that DAC could synergistically enhance myeloma cell sensitivity to BZM at least partly by regulating Wnt/β-catenin signaling. Our results can be used to optimize therapeutic regimens for MM.
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spelling pubmed-78484152021-02-16 Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/β-Catenin Pathway Jin, Yulong Xu, Li Wu, Xiaodong Feng, Juan Shu, Mimi Gu, Hongtao Gao, Guangxun Zhang, Jinyi Dong, Baoxia Chen, Xiequn Oncol Res Article Multiple myeloma (MM) is a hematopoietic malignancy characterized by the clonal proliferation of antibody-secreting plasma cells. Bortezomib (BZM), the first FDA-approved proteasome inhibitor, has significant antimyeloma activity and prolongs the median survival of MM patients. However, MM remains incurable predominantly due to acquired drug resistance and disease relapse. β-Catenin, a key effector protein in the canonical Wnt signaling pathway, has been implicated in regulating myeloma cell sensitivity to BZM. Decitabine (DAC) is an epigenetic modulating agent that induces tumor suppressor gene reexpression based on its gene-specific DNA hypomethylation. DAC has been implicated in modulating Wnt/β-catenin signaling by promoting the demethylation of the Wnt/β-catenin antagonists sFRP and DKK. In this study, we report the effects of single reagent DAC therapy and DAC combined with BZM on β-catenin accumulation, myeloma cell survival, apoptosis, and treatment sensitivity. Our study proved that DAC demethylated and induced the reexpression of the Wnt antagonists sFRP3 and DKK1. DAC also reduced GSK3β (Ser9) phosphorylation and decreased β-catenin accumulation in the nucleus, which were induced by BZM. Thus, the transcription of cyclin D1, c-Myc, and LEF/TCF was reduced, which synergistically inhibited cell proliferation, enhanced BZM-induced apoptosis, and promoted BZM-induced cell cycle arrest in myeloma cells. In summary, these results indicated that DAC could synergistically enhance myeloma cell sensitivity to BZM at least partly by regulating Wnt/β-catenin signaling. Our results can be used to optimize therapeutic regimens for MM. Cognizant Communication Corporation 2019-06-21 /pmc/articles/PMC7848415/ /pubmed/30837032 http://dx.doi.org/10.3727/096504018X15443011011637 Text en Copyright © 2019 Cognizant, LLC. http://creativecommons.org/licenses/by-nc-nd/4.0/ This article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License.
spellingShingle Article
Jin, Yulong
Xu, Li
Wu, Xiaodong
Feng, Juan
Shu, Mimi
Gu, Hongtao
Gao, Guangxun
Zhang, Jinyi
Dong, Baoxia
Chen, Xiequn
Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/β-Catenin Pathway
title Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/β-Catenin Pathway
title_full Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/β-Catenin Pathway
title_fullStr Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/β-Catenin Pathway
title_full_unstemmed Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/β-Catenin Pathway
title_short Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/β-Catenin Pathway
title_sort synergistic efficacy of the demethylation agent decitabine in combination with the protease inhibitor bortezomib for treating multiple myeloma through the wnt/β-catenin pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848415/
https://www.ncbi.nlm.nih.gov/pubmed/30837032
http://dx.doi.org/10.3727/096504018X15443011011637
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