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学科主题临床医学
Tetrandrine blocks autophagic flux and induces apoptosis via energetic impairment in cancer cells
Qiu, W.1,2,3; Su, M.4,5; Xie, F.1,2,3; Ai, J.6; Ren, Y.7; Zhang, J.1,2,3; Guan, R.1,2,3; He, W.8; Gong, Y.1,2,3; Guo, Y.1,2,3
关键词Tetrandrine Autophagy Lysosomes Apoptosis Metabolism
刊名CELL DEATH & DISEASE
2014-03-01
DOI10.1038/cddis.2014.84
5
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Cell Biology
研究领域[WOS]Cell Biology
关键词[WOS]HUMAN HEPATOCELLULAR-CARCINOMA ; IN-VITRO ; LYSOSOMAL PH ; TUMOR-CELLS ; RPE CELLS ; MECHANISMS ; CHLOROQUINE ; METABOLISM ; RESISTANCE ; THERAPY
英文摘要

Lysosomes are acidic organelles that have a crucial role in degrading intracellular macromolecules and organelles during the final stage of autophagy. Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, was reported as an autophagy activator. Here, in contrast with previous studies, we show that Tet is a potent lysosomal deacidification agent and is able to block autophagic flux in the degradation stage. Single-agent Tet induces significant apoptosis both in vitro and in xenograft models. In the presence of Tet, apoptosis was preceded by a robust accumulation of autophagosomes and an increased level of microtubule-associated protein 1 light chain 3, type II (LC3-II). However, Tet increased the level of sequestosome 1 and decreased the turnover of LC3, indicating the blockade of autophagic flux in the degradation stage. As blockade of autophagic flux decreases the recycling of cellular fuels, Tet reduces the uptake of glucose in cancer cells. These effects lead to insufficient substrates for tricarboxylic acid (TCA) cycle and impaired oxidative phosphorylation. Blunting autophagosome formation using 3-methyladenine or genetic knockdown of Beclin-1 failed to rescue cells upon Tet treatment. By contrast, addition of methyl pyruvate to supplement TCA substrates protected Tet-treated tumor cells. These results demonstrate that energetic impairment is required in Tet-induced apoptosis. Tet, as a potent lysosomal inhibitor, is translatable to the treatment of malignant tumor patients.

语种英语
WOS记录号WOS:000333754100027
引用统计
被引频次:29[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/52378
专题北京大学第一临床医学院_泌尿外科
北京大学药学院
北京大学第一临床医学院_检验科
北京大学第二临床医学院_乳腺外科
北京大学第三临床医学院_妇产科
北京大学临床肿瘤学院_肝胆胰外二科
作者单位1.Peking Univ, Hosp 1, Dept Urol, Beijing 100034, Peoples R China
2.Peking Univ, Inst Urol, Beijing 100034, Peoples R China
3.Natl Urol Canc Ctr, Beijing 100034, Peoples R China
4.Chinese Acad Med Sci, Peking Union Med Coll, FuWai Hosp, Sinogerman Lab Mol Med,State Key Lab Cardiovasc D, Beijing 100037, Peoples R China
5.Chinese Acad Med Sci, Peking Union Med Coll, Cardiovasc Inst, Beijing 100037, Peoples R China
6.Univ Pittsburgh, Dept Urol, Pittsburgh, PA 15232 USA
7.Peking Univ, Hosp 1, Lab Electron Microscopy, Beijing 100034, Peoples R China
8.Shandong Univ, Prov Hosp, Dept Urol, Jinan 250021, Peoples R China
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GB/T 7714
Qiu, W.,Su, M.,Xie, F.,et al. Tetrandrine blocks autophagic flux and induces apoptosis via energetic impairment in cancer cells[J]. CELL DEATH & DISEASE,2014,5.
APA Qiu, W..,Su, M..,Xie, F..,Ai, J..,Ren, Y..,...&Guo, Y..(2014).Tetrandrine blocks autophagic flux and induces apoptosis via energetic impairment in cancer cells.CELL DEATH & DISEASE,5.
MLA Qiu, W.,et al."Tetrandrine blocks autophagic flux and induces apoptosis via energetic impairment in cancer cells".CELL DEATH & DISEASE 5(2014).
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