PMID- 17690712 OWN - NLM STAT- MEDLINE DCOM- 20080122 LR - 20240109 IS - 1350-9047 (Print) IS - 1350-9047 (Linking) VI - 14 IP - 11 DP - 2007 Nov TI - A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase. PG - 1948-57 AB - 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. FAU - Xu, Z-X AU - Xu ZX AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Liang, J AU - Liang J FAU - Haridas, V AU - Haridas V FAU - Gaikwad, A AU - Gaikwad A FAU - Connolly, F P AU - Connolly FP FAU - Mills, G B AU - Mills GB FAU - Gutterman, J U AU - Gutterman JU LA - eng GR - CA 16672/CA/NCI NIH HHS/United States GR - P50-CA83639/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20070810 PL - England TA - Cell Death Differ JT - Cell death and differentiation JID - 9437445 RN - 0 (ATG5 protein, human) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Autophagy-Related Protein 5) RN - 0 (BECN1 protein, human) RN - 0 (Beclin-1) RN - 0 (Fusion Regulatory Protein 1, Heavy Chain) RN - 0 (Membrane Proteins) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Multienzyme Complexes) RN - 0 (RNA, Small Interfering) RN - 0 (Saponins) RN - 0 (TSC2 protein, human) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - 69451KN1RO (avicin D) RN - 886U3H6UFF (Chloroquine) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 6.2.1.45 (ATG7 protein, human) RN - EC 6.2.1.45 (Autophagy-Related Protein 7) RN - EC 6.2.1.45 (Ubiquitin-Activating Enzymes) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - AMP-Activated Protein Kinases MH - Apoptosis/physiology MH - Apoptosis Regulatory Proteins/metabolism MH - *Autophagy MH - Autophagy-Related Protein 5 MH - Autophagy-Related Protein 7 MH - Beclin-1 MH - Cell Line, Tumor MH - Chloroquine/pharmacology MH - Enzyme Activation MH - Fusion Regulatory Protein 1, Heavy Chain/metabolism MH - Humans MH - Membrane Proteins/metabolism MH - Microtubule-Associated Proteins/genetics/metabolism MH - Multienzyme Complexes/*metabolism MH - Protein Serine-Threonine Kinases/*metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - RNA, Small Interfering MH - Saponins/*pharmacology MH - Sirolimus/pharmacology MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Suppressor Proteins/genetics/metabolism MH - Ubiquitin-Activating Enzymes/genetics/*metabolism EDAT- 2007/08/11 09:00 MHDA- 2008/01/23 09:00 CRDT- 2007/08/11 09:00 PHST- 2007/08/11 09:00 [pubmed] PHST- 2008/01/23 09:00 [medline] PHST- 2007/08/11 09:00 [entrez] AID - 4402207 [pii] AID - 10.1038/sj.cdd.4402207 [doi] PST - ppublish SO - Cell Death Differ. 2007 Nov;14(11):1948-57. doi: 10.1038/sj.cdd.4402207. Epub 2007 Aug 10.