Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450.
2015
Online
academicJournal
Zugriff:
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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Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450.
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Autor/in / Beteiligte Person: | Cerella, C. ; Muller, Florian ; Gaigneaux, A. ; Radogna, F. ; Viry, E. ; Chateauvieux, S. ; Dicato, Mario ; Diederich, M. |
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Veröffentlichung: | 2015 |
Medientyp: | academicJournal |
DOI: | 10.1038/cddis.2015.134 |
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