Adipocytes cause leukemia cell resistance to daunorubicin via oxidative stress response

// Xia Sheng 1 , Jonathan Tucci 1 , Jean-Hugues Parmentier 1 , Lingyun Ji 2 , James W. Behan 1 , Nora Heisterkamp 3, 4, 5 , Steven D. Mittelman 1, 4, 6 1 Diabetes and Obesity Program, Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles, Los Angeles, CA, USA 2 Department of Biostatistics, Children’s Hospital Los Angeles, Los Angeles, CA, USA 3 Division of Hematology/Oncology and Bone Marrow Transplant, Children’s Hospital Los Angeles, Los Angeles, CA, USA 4 Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 5 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 6 Departments of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Correspondence to: Steven D. Mittelman, email: smittelman@chla.usc.edu Keywords: ALL, adipocyte, oxidative stress, glutathione, drug resistance Received: February 11, 2016      Accepted: September 19, 2016      Published: September 26, 2016 ABSTRACT Adipocytes promote cancer progression and impair treatment, and have been shown to protect acute lymphoblastic leukemia (ALL) cells from chemotherapies. Here we investigate whether this protection is mediated by changes in oxidative stress. Co-culture experiments showed that adipocytes protect ALL cells from oxidative stress induced by drugs or irradiation. We demonstrated that ALL cells induce intracellular ROS and an oxidative stress response in adipocytes. This adipocyte oxidative stress response leads to the secretion of soluble factors which protect ALL cells from daunorubicin (DNR). Collectively, our investigation shows that ALL cells elicit an oxidative stress response in adipocytes, leading to adipocyte protection of ALL cells against DNR.