Mature adipocytes in bone marrow protect myeloma cells against chemotherapy through autophagy activation.

Zhiqiang Liu,Qiang Tong,Nora M Navone,Jin He,Jingda Xu,Jing Yang,Huan Liu,Robert Z Orlowski,Pei Lin,Larry W Kwak,Xinhai Wan

doi:10.18632/oncotarget.6020

Zhiqiang Liu, Qiang Tong + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.6020

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Abstract

A major problem in patients with multiple myeloma is chemotherapy resistance, which develops in myeloma cells upon interaction with bone marrow stromal cells. However, few studies have determined the role of bone marrow adipocytes, a major component of stromal cells in the bone marrow, in myeloma chemotherapy resistance. We reveal that mature human adipocytes activate autophagy and upregulate the expression of autophagic proteins, thereby suppressing chemotherapy-induced caspase cleavage and apoptosis in myeloma cells. We found that adipocytes secreted known and novel adipokines, such as leptin and adipsin. The addition of these adipokines enhanced the expression of autophagic proteins and reduced apoptosis in myeloma cells. In vivo studies further demonstrated the importance of bone marrow-derived adipocytes in the reduced response of myeloma cells to chemotherapy. Our findings suggest that adipocytes, adipocyte-secreted adipokines, and adipocyte-activated autophagy are novel targets for combatting chemotherapy resistance and enhancing treatment efficacy in myeloma patients.

Highlights

Multiple myeloma (MM) is characterized by a clonal expansion of malignant plasma cells [1]
We found a lower percentage of apoptosis (Figure 7B), higher percentage of autophagy (Figure 7C), and upregulated levels of pStat3 (Figure 7D) in CD138+ MM cells from mice injected with MM cells and adipocytes than from those injected with MM cells only
A bone marrow stromal cells (BMSCs) that heavily infiltrates MM patients’ bone marrow (BM), are important in the induction of chemotherapy resistance

Summary

Introduction

Multiple myeloma (MM) is characterized by a clonal expansion of malignant plasma cells [1]. Strategies to overcome chemotherapy resistance in MM patients are urgently needed. Several cell types of BMSCs, including macrophages [11, 12], plasmacytoid dendritic cells [13], osteoblasts [14, 15], osteoclasts [1517], and immune cells [18], have been identified. These cells produce many cytokines that support MM growth and survival [19, 20].

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