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

// Zhiqiang Liu 1,* , Jingda Xu 1,* , Jin He 1 , Huan Liu 1 , Pei Lin 2 , Xinhai Wan 3 , Nora M. Navone 3 , Qiang Tong 4 , Larry W. Kwak 1 , Robert Z. Orlowski 1 and Jing Yang 1 1 Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Genitourinary Medical Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA * These authors have contributed equally to this work Correspondence to: Jing Yang, email: // Keywords : multiple myeloma, adipocytes, autophagy, apoptosis, chemotherapy resistance Received : June 30, 2015 Accepted : September 05, 2015 Published : October 07, 2015 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.