title: An Early and Robust Activation of Caspases Heads Cells for a Regulated Form of Necrotic-like Cell Death.
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 cell death. 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.
authors.affiliation: 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.
authors.forename: Mercè
authors.initials: M
authors.lastname: Garcia-Belinchón
authors.affiliation: 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.
authors.forename: María
authors.initials: M
authors.lastname: Sánchez-Osuna
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Martínez-Escardó
authors.affiliation: 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.
authors.forename: Carla
authors.initials: C
authors.lastname: Granados-Colomina
authors.affiliation: 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.
authors.forename: Sònia
authors.initials: S
authors.lastname: Pascual-Guiral
authors.affiliation: 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.
authors.forename: Victoria
authors.initials: V
authors.lastname: Iglesias-Guimarais
authors.affiliation: 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.
authors.forename: Elisenda
authors.initials: E
authors.lastname: Casanelles
authors.affiliation: Cell death 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.
authors.forename: Judit
authors.initials: J
authors.lastname: Ribas
authors.affiliation: 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. Electronic address: victor.yuste@uab.cat.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Yuste
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053119:Benzophenanthridines / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D003078:Colchicine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D009474:Neurons; D015739:Nocodazole / Q000494:pharmacology; D057786:Peptidomimetics / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013049:Spectrin
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D002352:Carrier Proteins; D020169:Caspases; D002843:Chromatin; D003078:Colchicine; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D015739:Nocodazole; D057786:Peptidomimetics; D011804:Quinolines; D012402:Rotenone; D019311:Staurosporine; D019284:Thapsigargin; D013049:Spectrin; C468548:quinoline-val-asp(OMe)-CH2-OPH; C476093:z-Val-Ala-Asp(Ome)-fluoromethylketone; C016299:chelerythrine
keywords: apoptosis; apoptotic nuclear morphology; caspase; cell death; chelerythrine; necrosis (necrotic death); oxidative stress; thiolic oxidative stress