A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase.
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.
Xu
Z-X
ZX
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Liang
J
J
Haridas
V
V
Gaikwad
A
A
Connolly
F P
FP
Mills
G B
GB
Gutterman
J U
JU
D055372:AMP-Activated Protein Kinases; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D004789:Enzyme Activation; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D012503:Saponins / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism*
C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D027282:Fusion Regulatory Protein 1, Heavy Chain; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009097:Multienzyme Complexes; D034741:RNA, Small Interfering; D012503:Saponins; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C478445:avicin D; D002738:Chloroquine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D020123:Sirolimus