A novel androstenedione derivative induces ROS-mediated autophagy and attenuates drug resistance in osteosarcoma by inhibiting macrophage migration inhibitory factor (MIF).
A novel androstenedione derivative induces ROS-mediated autophagy and attenuates drug resistance in osteosarcoma by inhibiting macrophage migration inhibitory factor (MIF).
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一种新型雄烯二酮衍生物通过抑制巨噬细胞迁移抑制因子（MIF）诱导ROS介导的自噬并减弱骨肉瘤的耐药性
DOI：
10.1038/cddis.2014.300
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发表时间：
2014-08-07
影响因子：
9
通讯作者：
Zhao, Y.
中科院分区：
文献类型：
--
作者：
Liu, Y.;Zhao, L.;Ju, Y.;Li, W.;Zhang, M.;Jiao, Y.;Zhang, J.;Wang, S.;Wang, Y.;Zhao, M.;Zhang, B.;Zhao, Y.
骨肉瘤是儿童和青少年常见的原发性骨肿瘤。骨肉瘤的耐药性导致其高致死率。巨噬细胞迁移抑制因子（MIF）是一种与乳腺癌化疗耐药有关的炎症相关细胞因子。本研究分离了一种新的雄烯二酮衍生物，鉴定为3,4 -二羟基- 9,10 -第二雄烯- 1,3,5,7 -四烯- 9,17 -二酮（DSTD）。DSTD可抑制MIF在MG-63和U2OS细胞中的表达。DSTD抑制MIF通过诱导Bcl-2下调和HMGB1易位促进自噬。n -乙酰- l-半胱氨酸（NAC）和3-甲基腺嘌呤（3-MA）可减弱DSTD诱导的自噬，但促进细胞死亡，提示DSTD诱导ros介导的自噬可挽救细胞死亡。然而，在化疗药物存在的情况下，DSTD通过降低HMGB1水平来增强化疗敏感性。我们的数据表明MIF抑制是克服骨肉瘤耐药的一种治疗策略。
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.
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