Combined disruption of both the MEK/ERK and the IL-6R/STAT3 pathways is required to induce apoptosis of multiple myeloma cells in the presence of bone marrow stromal cells

Item Type:	Article
Title:	Combined disruption of both the MEK/ERK and the IL-6R/STAT3 pathways is required to induce apoptosis of multiple myeloma cells in the presence of bone marrow stromal cells
Creators Name:	Chatterjee, M. and Stuehmer, T. and Herrmann, P. and Bommert, K. and Doerken, B. and Bargou, R.C.
Abstract:	The interleukin-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3) pathway contributes to the pathogenesis of multiple myeloma (MM) and protects MM cells from apoptosis. However, MM cells survive the IL-6R blockade if they are cocultured with bone marrow stromal cells (BMSCs), suggesting that the BM microenvironment stimulates IL-6–independent pathways that exert a pro-survival effect. The goal of this study was to investigate the underlying mechanism. Detailed pathway analysis revealed that BMSCs stimulate STAT3 via the IL-6R, and mitogen-activated protein (MAP) kinases via IL-6R–independent mechanisms. Abolition of MEK1,2 activity with PD98059, or ERK1,2 small interfering RNA knockdown, was insufficient to induce apoptosis. However, the combined disruption of the IL-6R/STAT3 and MEK1,2/ERK1,2 pathways led to strong induction of apoptosis even in the presence of BMSCs. This effect was observed with MM cell lines and with primary MM cells, suggesting that the BMSC-induced activation of MEK1,2/ERK1,2 renders MM cells IL-6R/STAT3 independent. Therefore, in the presence of cells from the BM micro-environment, combined targeting of different (and independently activated) pathways is required to efficiently induce apoptosis of MM cells. This might have direct implications for the development of future therapeutic strategies for MM.
Keywords:	Apoptosis, Bone Marrow Cells, Coculture Techniques, Cultured Tumor Cells, DNA-Binding Proteins, Interleukin-6 Receptors, MAP Kinase Kinase 1, Mitogen-Activated Protein Kinase 3, Multiple Myeloma, STAT3 Transcription Factor, Signal Transduction, Small Interfering RNA, Stromal Cells, Trans-Activators
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	104
Number:	12
Page Range:	3712-3721
Date:	1 January 2004
Official Publication:	https://doi.org/10.1182/blood-2004-04-1670
PubMed:	View item in PubMed

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