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Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450
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Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450
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Journal Article
Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450
2015
Overview
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.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 13/1
/ 13/106
/ 13/2
/ 13/31
/ 14
/ 14/34
/ 38
/ 38/89
/ 42
/ Anatomie (cytologie, histologie, embryologie...) & physiologie
/ Anatomy (cytology, histology, embryology...) & physiology
/ Antineoplastic Agents - pharmacology
/ Apoptosis/drug effects/physiology
/ Biomedical and Life Sciences
/ Down-Regulation - drug effects
/ Humans
/ Myeloid Cell Leukemia Sequence 1 Protein - biosynthesis
/ Myeloid Cell Leukemia Sequence 1 Protein - metabolism
/ Myeloid Cell Leukemia Sequence 1 Protein/biosynthesis/metabolism
/ Original
