期刊
CELL DEATH AND DIFFERENTIATION
卷 14, 期 11, 页码 1948-1957出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4402207
关键词
avicins; autophagy; tumor; AMPK
资金
- NCI NIH HHS [CA 16672, P50-CA83639] Funding Source: Medline
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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