RRC ID 12268
Author Morimoto S, Tanaka Y, Sasaki K, Tanaka H, Fukamizu T, Shoyama Y, Shoyama Y, Taura F.
Title Identification and characterization of cannabinoids that induce cell death through mitochondrial permeability transition in Cannabis leaf cells.
Journal J. Biol. Chem.
Abstract Cannabinoids are secondary metabolites stored in capitate-sessile glands on leaves of Cannabis sativa. We discovered that cell death is induced in the leaf tissues exposed to cannabinoid resin secreted from the glands, and identified cannabichromenic acid (CBCA) and Delta(1)-tetrahydrocannabinolic acid (THCA) as unique cell death mediators from the resin. These cannabinoids effectively induced cell death in the leaf cells or suspension-cultured cells of C. sativa, whereas pretreatment with the mitochondrial permeability transition (MPT) inhibitor cyclosporin A suppressed this cell death response. Examinations using isolated mitochondria demonstrated that CBCA and THCA mediate opening of MPT pores without requiring Ca(2+) and other cytosolic factors, resulting in high amplitude mitochondrial swelling, release of mitochondrial proteins (cytochrome c and nuclease), and irreversible loss of mitochondrial membrane potential. Therefore, CBCA and THCA are considered to cause serious damage to mitochondria through MPT. The mitochondrial damage was also confirmed by a marked decrease of ATP level in cannabinoid-treated suspension cells. These features are in good accord with those of necrotic cell death, whereas DNA degradation was also observed in cannabinoid-mediated cell death. However, the DNA degradation was catalyzed by nuclease(s) released from mitochondria during MPT, indicating that this reaction was not induced via a caspase-dependent apoptotic pathway. Furthermore, the inhibition of the DNA degradation only slightly blocked the cell death induced by cannabinoids. Based on these results, we conclude that CBCA and THCA have the ability to induce necrotic cell death via mitochondrial dysfunction in the leaf cells of C. sativa.
Volume 282(28)
Pages 20739-51
Published 2007-7-13
DOI 10.1074/jbc.M700133200
PII M700133200
PMID 17513301
MeSH Calcium / metabolism Cannabis / cytology Cannabis / metabolism* Caspases / metabolism Cell Membrane Permeability / drug effects Cyclosporine / pharmacology DNA Fragmentation / drug effects Dronabinol / analogs & derivatives* Dronabinol / metabolism* Dronabinol / pharmacology Mitochondria / metabolism* Mitochondrial Proteins / metabolism* Necrosis / metabolism Plant Leaves / cytology Plant Leaves / metabolism* Plant Proteins / metabolism*
IF 4.011
Times Cited 21
Arabidopsis / Cultured plant cells, genes rpc00001