C6 ceramide dramatically increases vincristine sensitivity both in vivo and in vitro, involving AMP-activated protein kinase-p53 signaling

被引:53
作者
Chen, Min-Bin [1 ]
Jiang, Qin [2 ]
Liu, Yuan-yuan [3 ]
Zhang, Yan [1 ]
He, Bang-shun [4 ]
Wei, Mu-Xin [5 ]
Lu, Jian-Wei [6 ,7 ]
Ji, Yong [8 ]
Lu, Pei-Hua [8 ,9 ]
机构
[1] Jiangsu Univ, Kunshan Peoples Hosp 1, Dept Oncol, Kunshan 215300, Jiangsu, Peoples R China
[2] Nanjing Med Univ, Affiliated Eye Hosp, Nanjing 210029, Jiangsu, Peoples R China
[3] Soochow Univ, Inst Neurosci, Suzhou 215021, Jiangsu, Peoples R China
[4] Nanjing Med Univ, Nanjing Hosp 1, Cent Lab, Nanjing 210006, Jiangsu, Peoples R China
[5] Nanjing Med Univ, Affiliated Hosp 1, Dept Tradit Chinese Med, Nanjing 210029, Jiangsu, Peoples R China
[6] Nanjing Med Univ, Dept Med Oncol, Affiliated Canc Hosp, Nanjing 210009, Jiangsu, Peoples R China
[7] Nanjing Med Univ, Wuxi Peoples Hosp, Dept Thorac Surg, Wuxi 214023, Jiangsu, Peoples R China
[8] Nanjing Med Univ, Wuxi Peoples Hosp, Dept Med Oncol, Wuxi 214023, Jiangsu, Peoples R China
[9] Nanjing Med Univ, Inst Integrated Tradit & Western Med, Dept Med, Ctr Oncol, Nanjing 210029, Jiangsu, Peoples R China
关键词
NON-APOPTOTIC DEATH; COLON-CANCER CELLS; MITOCHONDRIAL PERMEABILITY TRANSITION; GROWTH-INHIBITION; COLORECTAL-CANCER; MTORC1; INHIBITION; CYCLOPHILIN-D; SURVIVAL; CONTRIBUTES; PATHWAY;
D O I
10.1093/carcin/bgv094
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Use of the conventional cancer chemotherapy (i.e. vincristine) is limited in tumor cells exhibiting pre-existing or acquired resistance. Here, we found that C6 ceramide (C6) dramatically sensitized vincristine's activity. In vitro, C6 and vincristine coadministration induced substantial necrosis and apoptosis in multiple human cancer cell lines, which were accompanied by a profound AMP-activated protein kinase (AMPK) activation, subsequent p53 activation, mTORC1 inactivation and Bcl-2/HIF-1 alpha downregulation. Such synergistic effects were attenuated by AMPK inactivation through genetic mutation or short hairpin RNA silencing. Coadministration-activated p53 translocated to mitochondria, and formed a complex with cyclophilin-D, leading to mitochondrial permeability transition pore opening and cell necrosis. Disrupting p53-Cyp-D complexation through pharmacological or genetic means reduced costimulation-induced cytotoxicity. In vivo, a liposomal C6 was synthesized, which dramatically enhanced the antiproliferative activity of vincristine on HCT-116 or A2780 xenografts. Together, C6 sensitizes vincristine-induced anticancer activity in vivo and in vitro, involving activating AMPK-p53 signaling.
引用
收藏
页码:1061 / 1070
页数:10
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