Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450.

Antineoplastic Agents/pharmacology; Apoptosis/drug effects/physiology; Calotropis/metabolism; Cardenolides/pharmacology; Cell Line, Tumor; Down-Regulation/drug effects; Humans; Jurkat Cells; Leupeptins/pharmacology; MCF-7 Cells; Myeloid Cell Leukemia Sequence 1 Protein/biosynthesis/metabolism; Proto-Oncogene Proteins c-bcl-2/metabolism; Transcription, Genetic/genetics; bcl-X Protein/metabolism

Abstract :

[en] 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.

Disciplines :

Anatomy (cytology, histology, embryology...) & physiology

Author, co-author :

Cerella, C.

Muller, Florian ; Université de Liège - ULiège > Cancer-Molecular Angiogenesis Laboratory

Gaigneaux, A.

Radogna, F.

Viry, E.

Chateauvieux, S.

Dicato, Mario

Diederich, M.

Language :

English

Title :

Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450.

Publication date :

2015

Journal title :

Cell death & disease

eISSN :

2041-4889

Volume :

Pages :

e1782

Peer reviewed :

Peer reviewed

Available on ORBi :

since 28 May 2019

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