title: Doxorubicin Regulates Autophagy Signals via Accumulation of Cytosolic Ca2+in Human Cardiac Progenitor Cells.
abstract: Doxorubicin (DOXO) is widely used to treat solid tumors. However, its clinical use is limited by side effects including serious cardiotoxicity due to cardiomyocyte damage. Resident cardiac progenitor cells (hCPCs) act as key regulators of homeostasis in myocardial cells. However, little is known about the function of hCPCs in DOXO-induced cardiotoxicity. In this study, we found that DOXO-mediated hCPC toxicity is closely related to calcium-related autophagy signaling and was significantly attenuated by blocking mTOR signaling in human hCPCs. DOXO induced hCPC apoptosis with reduction of SMP30 (regucalcin) and autophagosome marker LC3, as well as remarkable induction of the autophagy-related markers, Beclin-1, APG7, and P62/SQSTM1 and induction of calcium-related molecules, CaM (Calmodulin) and CaMKII (Calmodulin kinase II). The results of an LC3 puncta assay further indicated that DOXO reduced autophagosome formation via accumulation of cytosolic Ca2+. Additionally, DOXO significantly induced mTOR expression in hCPCs, and inhibition of mTOR signaling by rapamycin, a specific inhibitor, rescued DOXO-mediated autophagosome depletion in hCPCs with significant reduction of DOXO-mediated cytosolic Ca2+accumulation in hCPCs, and restored SMP30 and mTOR expression. Thus, DOXO-mediated hCPC toxicity is linked to Ca2+-related autophagy signaling, and inhibition of mTOR signaling may provide a cardio-protective effect against DOXO-mediated hCPC toxicity.
authors.affiliation: Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Korea. siwonvin@naver.com.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Park
authors.affiliation: Cellular Therapeutics Team, Bio Reseach and Development Center, Daewoong Pham. Co., Ltd., Seoul 06170, Korea. shchoi0704@naver.com.
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Thoracic and Cardiovascular Surgery; Pusan National University Yangsan Hospital, Yangsan 50612, Korea. 2719k@naver.com.
authors.forename: Hyungtae
authors.initials: H
authors.lastname: Kim
authors.affiliation: Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Korea. jst5396@hanmail.net.
authors.forename: Seung Taek
authors.initials: ST
authors.lastname: Ji
authors.affiliation: Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Korea. jangwoongbi@naver.com.
authors.forename: Woong Bi
authors.initials: WB
authors.lastname: Jang
authors.affiliation: Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, Yangsan 50612, Korea. jhkimst@pusan.ac.kr.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Cardiology, Seoul St. Mary's Hospital, School of Medicine, The Catholic University of Korea, Seoul 06591, Korea. whitesh@catholic.ac.kr.
authors.forename: Sang Hong
authors.initials: SH
authors.lastname: Baek
authors.affiliation: Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Korea. smkwon323@hotmail.com.|Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, Yangsan 50612, Korea. smkwon323@hotmail.com.
authors.forename: Sang Mo
authors.initials: SM
authors.lastname: Kwon
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1 / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D000071186:Beclin-1; D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C513323:RGN protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D004317:Doxorubicin; D019009:Proto-Oncogene Proteins c-kit; D058570:TOR Serine-Threonine Kinases; D002118:Calcium; D020123:Sirolimus
keywords: autophagy; cardiac progenitor cell; cardiotoxicity; doxorubicin; rapamycin