Cytotoxic effects and apoptotic signalling mechanisms of the sesquiterpenoid euplotin C, a secondary metabolite of the marine ciliate Euplotes crassus, in tumour cells |
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Authors: | D Cervia D Martini M Garcia-Gil G Di Giuseppe G Guella F Dini P Bagnoli |
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Institution: | (1) Dipartimento di Fisiologia e Biochimica “G. Moruzzi”, via S. Zeno, 56127 Pisa, Italy;(2) Dipartimento di Etologia, Ecologia ed Evoluzione, Università di Pisa, 56127 Pisa, Italy;(3) Dipartimento di Fisica, Laboratorio di Chimica bioorganica, Università di Trento, 38050 Trento, Italy |
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Abstract: | 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. |
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Keywords: | Ca2+stores caspases cell death cytochrome c endoplasmic reticulum |
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