Anti-β2-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy
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Mingjun Zhang1,2, Jin He1, Zhiqiang Liu1, Yong Lu1,2, Yuhuan Zheng1,2, Haiyan Li1,2, Jingda Xu1, Huan Liu1, Jianfei Qian1,2, Robert Z. Orlowski1, Larry W. Kwak1, Qing Yi1,2, Jing Yang1,3
1Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
3Cancer Research Institute and Cancer Hospital, Guangzhou Medical University, Guangzhou, China
Jing Yang, e-mail: [email protected]
Qing Yi, e-mail: [email protected]
Keywords: multiple myeloma, anti-β2M monoclonal antibody, bortezomib, autophagy, NF-κ p65
Received: November 17, 2014 Accepted: January 29, 2015 Published: March 31, 2015
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.
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