A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase

被引:0
作者
Z-X Xu
J Liang
V Haridas
A Gaikwad
F P Connolly
G B Mills
J U Gutterman
机构
[1] The University of Texas MD Anderson Cancer Center,Department of Systems Biology
[2] Current address: Department of Pediatric–Hematology–Oncology,undefined
[3] Baylor College of Medicine,undefined
[4] Houston,undefined
[5] TX,undefined
[6] USA.,undefined
来源
Cell Death & Differentiation | 2007年 / 14卷
关键词
avicins; autophagy; tumor; AMPK;
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中图分类号
学科分类号
摘要
Avicins, a family of plant triterpene electrophiles, can trigger apoptosis-associated tumor cell death, and suppress chemical-induced carcinogenesis by its anti-inflammatory, anti-mutagenic, and antioxidant properties. Here, we show that tumor cells treated with benzyloxycarbonylvalyl-alanyl–aspartic acid (O-methyl)–fluoro-methylketone, an apoptosis inhibitor, and Bax−/−Bak−/− apoptosis-resistant cells can still undergo cell death in response to avicin D treatment. We demonstrate that this non-apoptotic cell death is mediated by autophagy, which can be suppressed by chloroquine, an autophagy inhibitor, and by specific knockdown of autophagy-related gene-5 (Atg5) and Atg7. Avicin D decreases cellular ATP levels, stimulates the activation of AMP-activated protein kinase (AMPK), and inhibits mammalian target of rapamycin (mTOR) and S6 kinase activity. Suppression of AMPK by compound C and dominant-negative AMPK decreases avicin D-induced autophagic cell death. Furthermore, avicin D-induced autophagic cell death can be abrogated by knockdown of tuberous sclerosis complex 2 (TSC2), a key mediator linking AMPK to mTOR inhibition, suggesting that AMPK activation is a crucial event targeted by avicin D. These findings indicate the therapeutic potential of avicins by triggering autophagic cell death.
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页码:1948 / 1957
页数:9
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