Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-κB activity in myeloma cells

Molecular Cancer

Research

Yufang Shi¹  Guangwu Xu¹  Shelby L O'Connor²  Stephanie Markovina³  Shigeki Miyamoto⁴  Jaehyup Kim⁵  Parul Trivedi⁵  Natalie S Callander⁶  Peiman Hematti⁶  KyungMann Kim⁷  Catherine P Leith⁸ 

[1] Department of Molecular Genetics, Microbiology and Immunology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 150 Bergen Street, 07103, Newark, New Jersey, USA;Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, 50 Highland Avenue, 53705, Madison, Wisconsin, USA;Program in Cellular and Molecular Biology and Medical Science Training Program, University of Wisconsin School of Medicine and Public Health, 750 Highland Avenue, 53705, Madison, Wisconsin, USA;Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, 50 Highland Avenue, 53705, Madison, Wisconsin, USA;Program in Cellular and Molecular Biology and Medical Science Training Program, University of Wisconsin School of Medicine and Public Health, 750 Highland Avenue, 53705, Madison, Wisconsin, USA;Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, 50 Highland Avenue, 53705, Madison, Wisconsin, USA;University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, 750 Highland Avenue, 53705, Madison, Wisconsin, USA;Section of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 750 Highland Avenue, 53705, Madison, Wisconsin, USA;Section of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 750 Highland Avenue, 53705, Madison, Wisconsin, USA;University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, 750 Highland Avenue, 53705, Madison, Wisconsin, USA;University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, 750 Highland Avenue, 53705, Madison, Wisconsin, USA;Department of Biotatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, 750 Highland Avenue, 53705, Madison, Wisconsin, USA;University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, 750 Highland Avenue, 53705, Madison, Wisconsin, USA;University of Wisconsin Division of Hematopathology, Department of Pathology, University of Wisconsin School of Medicine and Public Health, 750 Highland Avenue, 53705, Madison, Wisconsin, USA;

关键词: Multiple Myeloma;    Conditioned Medium;    Bortezomib;    Lenalidomide;    Electrophoretic Mobility Shift Assay;   

DOI  :  10.1186/1476-4598-9-176

 received in 2010-01-19, accepted in 2010-07-06,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundComponents of the microenvironment such as bone marrow stromal cells (BMSCs) are well known to support multiple myeloma (MM) disease progression and resistance to chemotherapy including the proteasome inhibitor bortezomib. However, functional distinctions between BMSCs in MM patients and those in disease-free marrow are not completely understood. We and other investigators have recently reported that NF-κB activity in primary MM cells is largely resistant to the proteasome inhibitor bortezomib, and that further enhancement of NF-κB by BMSCs is similarly resistant to bortezomib and may mediate resistance to this therapy. The mediating factor(s) of this bortezomib-resistant NF-κB activity is induced by BMSCs is not currently understood.ResultsHere we report that BMSCs specifically derived from MM patients are capable of further activating bortezomib-resistant NF-κB activity in MM cells. This induced activity is mediated by soluble proteinaceous factors secreted by MM BMSCs. Among the multiple factors evaluated, interleukin-8 was secreted by BMSCs from MM patients at significantly higher levels compared to those from non-MM sources, and we found that IL-8 contributes to BMSC-induced NF-κB activity.ConclusionsBMSCs from MM patients uniquely enhance constitutive NF-κB activity in MM cells via a proteinaceous secreted factor in part in conjunction with IL-8. Since NF-κB is known to potentiate MM cell survival and confer resistance to drugs including bortezomib, further identification of the NF-κB activating factors produced specifically by MM-derived BMSCs may provide a novel biomarker and/or drug target for the treatment of this commonly fatal disease.

【 授权许可】

Unknown   
© Markovina et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.