ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells.
The bone marrow microenvironment facilitates the proliferation and survival of leukemia cells, contributing to disease relapse. Bone marrow-derived mesenchymal stem cells (MSCs) are well known to promote cancer chemoresistance via soluble factors and cell adhesion. However, little is known about the effects of MSCs on the mitochondrial dynamics of T-cell acute lymphoblastic leukemia (T-ALL) cells, or how this may influence the chemoresistance of these cells. Here, we tested both indirect (Transwell) and direct coculture strategies, and found that MSCs protected T-ALL cells from chemotherapeutic cell death and cytotoxicity under both culture conditions. In addition, cell viability was higher in the direct contact system compared with the Transwell system. We further showed that exposure of T-ALL cells to MSCs decreased mitochondrial reactive oxygen species (ROS) levels and promoted a pro-glycolytic shift that was characterized by increased glucose uptake and lactate production with concomitant reductions in adenosine triphosphate production and mitochondrial membrane potential. In T-ALL cells cocultured with MSCs, the mitochondrial morphology of T-ALL cells were altered from elongation to fragmentation because of the extracellular signal-regulated kinase activation-mediated phosphorylation of the pro-fission factor, dynamin-related protein 1 (Drp1), at residue S616. Consistent with this, the expression of S616-phosphorylated Drp1 recapitulated the mitochondrial dynamics, mitochondrial ROS levels, metabolic switching and chemoresistance seen in T-ALL cells cocultured with MSCs. These findings suggest that the ability of MSCs to trigger Drp1 activation-induced changes in mitochondrial dynamics is crucial to their ability to protect cells against chemotherapeutic agents.
Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.|Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.|Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Jianye
J
Cai
Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.|Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.|Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Jiancheng
J
Wang
Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.|Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.|Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Yinong
Y
Huang
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
Haoxiang
H
Wu
Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.|Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Ting
T
Xia
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
Jiaqi
J
Xiao
Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.|Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
Xiaoyong
X
Chen
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
Hongyu
H
Li
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
Yuan
Y
Qiu
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
Yingnan
Y
Wang
Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.|Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
Tao
T
Wang
Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Huimin
H
Xia
Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Qi
Q
Zhang
Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.|Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.|Biotherapy Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.|Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Andy Peng
AP
Xiang
D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D018920:Coculture Techniques; D019610:Cytoprotection / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D034281:Dynamins; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins