Open Access

ARTICLE

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

Yulong Jin^*, Li Xu^*, Xiaodong Wu^†, Juan Feng^*, Mimi Shu^*, Hongtao Gu^*, Guangxun Gao^*, Jinyi Zhang^‡, Baoxia Dong^*, Xiequn Chen^*

* Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, P.R. China
† Department of Cell Biology, Fourth Military Medical University, Xi’an, Shaanxi, P.R. China
‡ Department of School of Life Sciences, Jinzhou Medical University, Jinzhou, Liaoning, P.R. China

Oncology Research 2019, 27(6), 729-737. https://doi.org/10.3727/096504018X15443011011637

Abstract

Multiple myeloma (MM) is a hematopoietic malignancy characterized by the clonal proliferation of antibodysecreting 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. -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/ -catenin signaling by promoting the demethylation of the Wnt/ -catenin antagonists sFRP and DKK. In this study, we report the effects of single reagent DAC therapy and DAC combined with BZM on -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 GSK3 (Ser9) phosphorylation and decreased -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/ -catenin signaling. Our results can be used to optimize therapeutic regimens for MM.

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