Anti-β2-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy

Mingjun Zhang, Jin He, Zhiqiang Liu, Yong Lu, Yuhuan Zheng, Haiyan Li, Jingda Xu, Huan Liu, Jianfei Qian, Robert Z. Orlowski, Larry W. Kwak, Qing Yi, Jing Yang

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Our previous studies showed that anti-β2M monoclonal antibodies (mAbs) have strong and direct apoptotic effects on multiple myeloma (MM) cells, suggesting that anti-β2M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the anti-MM effects of combination treatment with anti-β2M mAbs and bortezomib (BTZ). Our results showed that anti-β2M mAbs enhanced BTZ-induced apoptosis of MM cell lines and primary MM cells. Combination treatment could also induce apoptosis of BTZ-resistant MM cells, and the enhanced effect depended on the surface expression of β2M on MM cells. BTZ up-regulated the expression of autophagy proteins, whereas combination with anti-β2M mAbs inhibited autophagy. Sequence analysis of the promoter region of beclin 1 identified 3 putative NF-κB-binding sites from -615 to -789 bp. BTZ treatment increased, whereas combination with anti-β2M mAbs reduced, NF-κB transcription activities in MM cells, and combination treatment inhibited NF-κB p65 binding to the beclin 1 promoter. Furthermore, anti-β2M mAbs and BTZ combination treatment had anti-MM activities in an established MM mouse model. Thus, our studies provide new insight and support for the clinical development of an anti-β2M mAb and BTZ combination treatment to overcome BTZ drug resistance and improve MM patient survival.

Original languageEnglish (US)
Pages (from-to)8567-8578
Number of pages12
JournalOncotarget
Volume6
Issue number11
DOIs
StatePublished - Jan 1 2015

Keywords

  • Anti-βM monoclonal antibody
  • Autophagy
  • Bortezomib
  • Multiple myeloma
  • NF-κ p65

ASJC Scopus subject areas

  • Oncology

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