Cytotoxic effects and apoptotic signalling mechanisms of the sesquiterpenoid euplotin C, a secondary metabolite of the marine ciliate Euplotes crassus, in tumour cells.
Most antitumour agents with cytotoxic properties induce apoptosis. The lipophilic compound euplotin C, isolated from the ciliate Euplotes crassus, is toxic to a number of different opportunistic or pathogenic microorganisms, although its mechanism of action is currently unknown. We report here that euplotin C is a powerful cytotoxic and pro-apoptotic agent in mouse AtT-20 and rat PC12 tumour-derived cell lines. In addition, we provide evidence that euplotin C treatment results in rapid activation of ryanodine receptors, depletion of Ca2+ stores in the endoplasmic reticulum (ER), the release of cytochrome c from the mitochondria, activation of caspase-12, and activation of caspase-3, leading to apoptosis. Intracellular Ca2+ overload is an early event which induces apoptosis and is parallelled by ER stress and the release of cytochrome c, whereas caspase-12 may be activated by euplotin C at a later stage in the apoptosis pathway. These events, either independently or concomitantly, lead to the activation of the caspase-3 and its downstream effectors, triggering the cell to undergo apoptosis. These results demonstrate that euplotin C may be considered for the design of cytotoxic and pro-apoptotic new drugs.
Dipartimento di Fisiologia e Biochimica G. Moruzzi, via S. Zeno, 56127, Pisa, Italy. d.cervia@dfb.unipi.it
D
D
Cervia
D
D
Martini
M
M
Garcia-Gil
G
G
Di Giuseppe
G
G
Guella
F
F
Dini
P
P
Bagnoli
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D016812:Euplotes / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D015394:Molecular Structure; D008970:Molecular Weight; D016716:PC12 Cells; D010911:Pituitary Neoplasms / Q000473:pathology; D051381:Rats; D012717:Sesquiterpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity*; D021241:Spectrometry, Mass, Electrospray Ionization
D012717:Sesquiterpenes; C493253:euplotin C; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium