Bax-derived membrane-active peptides act as potent and direct inducers of apoptosis in cancer cells.

TitleBax-derived membrane-active peptides act as potent and direct inducers of apoptosis in cancer cells.
Publication TypeJournal Article
Year of Publication2011
AuthorsValero, JGarcia, Sancey, L, Kucharczak, J, Guillemin, Y, Gimenez, D, Prudent, J, Gillet, G, Salgado, J, Coll, J-L, Aouacheria, A
JournalJ Cell Sci
Volume124
IssuePt 4
Pagination556-64
Date Published2011 Feb 15
ISSN1477-9137
KeywordsAnimals, Antineoplastic Agents, Apoptosis, bcl-2-Associated X Protein, Cell Line, Tumor, Cytochromes c, Humans, Mice, Mitochondria, Neoplasms, Peptides, Protein Structure, Tertiary
Abstract

Although many cancer cells are primed for apoptosis, they usually develop resistance to cell death at several levels. Permeabilization of the outer mitochondrial membrane, which is mediated by proapoptotic Bcl-2 family members such as Bax, is considered as a point of no return for initiating apoptotic cell death. This crucial role has placed Bcl-2 family proteins as recurrent targets for anticancer drug development. Here, we propose and demonstrate a new concept based on minimal active versions of Bax to induce cell death independently of endogenous Bcl-2 proteins. We show that membrane-active segments of Bax can directly induce the release of mitochondria-residing apoptogenic factors and commit tumor cells promptly and irreversibly to caspase-dependent apoptosis. On this basis, we designed a peptide encompassing part of the Bax pore-forming domain, which can target mitochondria, induce cytochrome c release and trigger caspase-dependent apoptosis. Moreover, this Bax-derived 'poropeptide' produced effective tumor regression after peritumoral injection in a nude mouse xenograft model. Thus, peptides derived from proteins that form pores in the mitochondrial outer membrane represent novel templates for anticancer agents.

DOI10.1242/jcs.076745
Alternate JournalJ. Cell. Sci.
Citation Key10.1242/jcs.076745
PubMed ID21245196
PubMed Central IDPMC3428271