Journal
JOURNAL OF CELL SCIENCE
Volume 124, Issue 4, Pages 556-564Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.076745
Keywords
Cytotoxicity; Anticancer activity; Apoptosis; Bcl-2 family; Mitochondria; Pore-forming peptides; Proapoptotic Bax
Categories
Funding
- La Region Rhone-Alpes
- ANR PNANO
- Silab-Jean Paufique Corporate Foundation (France)
- La Ligue Contre le Cancer (Comites de la Drome et du Rhone)
- Spanish MEC [BFU2007-67097, HF2007-0090]
- EGIDE PHC PICASSO, French [17092SM]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available