Journal
CELL DEATH & DISEASE
Volume 6, Issue -, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/cddis.2015.134
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Funding
- Marian Aldred Award
- ThinkPinkLux
- Europadonna Luxembourg
- Action LIONS 'Vaincre le Cancer'
- Televie grants (Fonds National de la Recherche Scientifique, Belgium)
- Fondation de Recherche Cancer et Sang
- Recherches Scientifiques Luxembourg association
- Een Haerz fir kriibskrank Kanner association
- Action LIONS Vaincre le Cancer association
- European Union [215009]
- Televie Luxembourg
- company Unibioscreen (Bruxelles, Belgium)
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University
- National Research Foundation (NRF) by the MEST of Korea [2012-0001184]
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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.
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