title: A novel androstenedione derivative induces ROS-mediated autophagy and attenuates drug resistance in osteosarcoma by inhibiting macrophage migration inhibitory factor (MIF).
abstract: Osteosarcoma is a common primary bone tumor in children and adolescents. The drug resistance of osteosarcoma leads to high lethality. Macrophage migration inhibitory factor (MIF) is an inflammation-related cytokine implicated in the chemoresistance of breast cancer. In this study, we isolated a novel androstenedione derivative identified as 3,4-dihydroxy-9,10-secoandrosta-1,3,5,7-tetraene-9,17-dione (DSTD). DSTD could inhibit MIF expression in MG-63 and U2OS cells. The inhibition of MIF by DSTD promoted autophagy by inducing Bcl-2 downregulation and the translocation of HMGB1. N-acetyl-L-cysteine (NAC) and 3-methyladenine (3-MA) attenuated DSTD-induced autophagy but promoted cell death, suggesting that DSTD induced ROS-mediated autophagy to rescue cell death. However, in the presence of chemotherapy drugs, DSTD enhanced the chemosensitivity by decreasing the HMGB1 level. Our data suggest MIF inhibition as a therapeutic strategy for overcoming drug resistance in osteosarcoma.
authors.affiliation: Department of Laboratory Medicine, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1] The Second Department Of Endocrinology, the Central Hospital Of Taian, Taian, China [2] Department Of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Laboratory Medicine, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ju
authors.affiliation: Department of Joint Surgery, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Central Laboratory, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Department of Central Laboratory, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Laboratory Medicine, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Central Laboratory, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000735:Androstenedione / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity*; D001343:Autophagy / Q000187:drug effects*; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012632:Secosteroids / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D014178:Translocation, Genetic
chemical_list: C000600929:3,4-dihydroxy-9,10-secoandrosta-1,3,5,7-tetraene-9,17-dione; D024243:HMGB1 Protein; D008263:Macrophage Migration-Inhibitory Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012632:Secosteroids; D000735:Androstenedione; C025946:3-methyladenine; D000225:Adenine; D000111:Acetylcysteine
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