An Early and Robust Activation of Caspases Heads Cells for a Regulated Form of Necrotic-like Cell Death

Journal Reference

J Biol Chem. 2015;290(34):20841-55.

Garcia-Belinchón M¹, Sánchez-Osuna M¹, Martínez-Escardó L², Granados-Colomina C², Pascual-Guiral S², Iglesias-Guimarais V¹, Casanelles E¹, Ribas J³,Yuste VJ⁴.

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From the Cell Death, Senescence and Survival group, Departament de Bioquímica i Biologia Molecular-Unitat de Medicina and Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Cerdanyola del Vallès, Barcelona, Spain, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Cerdanyola del Vallès, Barcelona, Spain, and.
From the Cell Death, Senescence and Survival group, Departament de Bioquímica i Biologia Molecular-Unitat de Medicina and Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Cerdanyola del Vallès, Barcelona, Spain.
Celldeath regulation by non-coding RNA group, Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Avinguda Rovira Roure 80, 25198 Lleida, Spain.
From the Cell Death, Senescence and Survival group, Departament de Bioquímica i Biologia Molecular-Unitat de Medicina and Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Cerdanyola del Vallès, Barcelona, Spain, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Cerdanyola del Vallès, Barcelona, Spain, and [email protected] [/expand].

Abstract

Apoptosis is triggered by the activation of caspases and characterized by chromatin condensation and nuclear fragmentation (type II nuclear morphology). Necrosis is depicted by a gain in cell volume (oncosis), swelling of organelles, plasma membrane leakage, and subsequent loss of intracellular contents. Although considered as different cell death entities, there is an overlap between apoptosis and necrosis. In this sense, mounting evidence suggests that both processes can be morphological expressions of a common biochemical network known as “apoptosis-necrosis continuum.” To gain insight into the events driving the apoptosis-necrosis continuum, apoptotically proficient cells were screened facing several apoptotic inducers for the absence of type II apoptotic nuclear morphologies. Chelerythrine was selected for further studies based on its cytotoxicity and the lack of apoptotic nuclear alterations. Chelerythrine triggered an early plasma membrane leakage without condensed chromatin aggregates. Ultrastructural analysis revealed that chelerythrine-mediated cytotoxicity was compatible with a necrotic-like type of cell death. Biochemically, chelerythrine induced the activation of caspases. Moreover, the inhibition of caspases prevented chelerythrine-triggered necrotic-like cell death. Compared with staurosporine, chelerythrine induced stronger caspase activation detectable at earlier times. After using a battery of chemicals, we found that high concentrations of thiolic antioxidants fully prevented chelerythrine-driven caspase activation and necrotic-like celldeath. Lower amounts of thiolic antioxidants partially prevented chelerythrine-mediated cytotoxicity and allowed cells to display type II apoptotic nuclear morphology correlating with a delay in caspase-3 activation. Altogether, these data support that an early and pronounced activation of caspases can drive cells to undergo a form of necrotic-like regulated cell death.

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