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

Abstract

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.

• Authors: Z-X Xu, J Liang, V Haridas, A Gaikwad, F P Connolly, G B Mills, J U Gutterman
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 14 Issue 11 Pg. 1948-57 (Nov 2007) ISSN: 1350-9047 [Print] England
• PMID: 17690712 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATG5 protein, human
• Apoptosis Regulatory Proteins
• Autophagy-Related Protein 5
• BECN1 protein, human
• Beclin-1
• Fusion Regulatory Protein 1, Heavy Chain
• Membrane Proteins
• Microtubule-Associated Proteins
• Multienzyme Complexes
• RNA, Small Interfering
• Saponins
• TSC2 protein, human
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• avicin D
• Chloroquine
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• AMP-Activated Protein Kinases
• Atg7 protein, human
• Autophagy-Related Protein 7
• Ubiquitin-Activating Enzymes
• Sirolimus

Topics

• AMP-Activated Protein Kinases
• Apoptosis (physiology)
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy
• Autophagy-Related Protein 5
• Autophagy-Related Protein 7
• Beclin-1
• Cell Line, Tumor
• Chloroquine (pharmacology)
• Enzyme Activation
• Fusion Regulatory Protein 1, Heavy Chain (metabolism)
• Humans
• Membrane Proteins (metabolism)
• Microtubule-Associated Proteins (genetics, metabolism)
• Multienzyme Complexes (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering
• Saponins (pharmacology)
• Sirolimus (pharmacology)
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (genetics, metabolism)
• Ubiquitin-Activating Enzymes (genetics, metabolism)