Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450
| العنوان: | Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450 |
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| المؤلفون: | Flavia Radogna, Anthoula Gaigneaux, Claudia Cerella, Elodie Viry, Mario Dicato, Sébastien Chateauvieux, Florian Muller, Marc Diederich |
| المصدر: | Cell Death & Disease CELL DEATH & DISEASE(6) |
| بيانات النشر: | Nature Publishing Group, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Cancer Research, Programmed cell death, Transcription, Genetic, Leupeptins, Immunology, bcl-X Protein, Down-Regulation, Antineoplastic Agents, Apoptosis, Pharmacology, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Jurkat Cells, Downregulation and upregulation, Cell Line, Tumor, MG132, medicine, Humans, Caspase, Cardiac glycoside, biology, Cell Biology, Proscillaridin, Cardenolides, Calotropis, chemistry, Biochemistry, Proto-Oncogene Proteins c-bcl-2, biology.protein, Proteasome inhibitor, MCF-7 Cells, Myeloid Cell Leukemia Sequence 1 Protein, Original Article, medicine.drug |
| الوصف: | Cardiac glycosides (CGs), prescribed to treat cardiovascular alterations, display potent anti-cancer activities. Despite their well-established target, the sodium/potassium (Na+/K+)-ATPase, downstream mechanisms remain poorly elucidated. UNBS1450 is a hemi-synthetic cardenolide derived from 2″-oxovorusharin extracted from the plant Calotropis procera, which is effective against various cancer cell types with an excellent differential toxicity. By comparing adherent and non-adherent cancer cell types, we validated Mcl-1 as a general and early target of UNBS1450. A panel of CGs including cardenolides ouabain, digitoxin and digoxin as well as bufadienolides cinobufagin and proscillaridin A allowed us to generalize our findings. Our results show that Mcl-1, but not Bcl-xL nor Bcl-2, is rapidly downregulated prior to induction of apoptosis. From a mechanistic point of view, we exclude an effect on transcription and demonstrate involvement of a pathway affecting protein stability and requiring the proteasome in the early CG-induced Mcl-1 downregulation, without the involvement of caspases or the BH3-only protein NOXA. Strategies aiming at preventing UNBS1450-induced Mcl-1 downregulation by overexpression of a mutated, non-ubiquitinable form of the protein or the use of the proteasome inhibitor MG132 inhibited the compound’s ability to induce apoptosis. Altogether our results point at Mcl-1 as a ubiquitous factor, downregulated by CGs, whose modulation is essential to achieve cell death. |
| اللغة: | English |
| تدمد: | 2041-4889 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0fb52abe959b7aec2bf389e5e8669af5Test http://europepmc.org/articles/PMC4669823Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0fb52abe959b7aec2bf389e5e8669af5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20414889 |
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