Peer-Reviewed Journal Details
Mandatory Fields
Finnegan, NM,Curtin, JF,Prevost, G,Morgan, B,Cotter, TG;
2001
January
British Journal of Cancer
Induction of apoptosis in prostate carcinoma cells by BH3 peptides which inhibit Bak/Bcl-2 interactions
Validated
()
Optional Fields
prostate apoptosis BH3 Bcl-2 peptide PROTOONCOGENE BCL-2 MEDIATED APOPTOSIS CANCER CELLS BAX DEATH PROTEIN DOMAIN HETERODIMERIZATION DISTINCT FAMILY
85
115
121
Interactions between proteins of the Bcl-2 family play an important role in the regulation of apoptosis. Anti-apoptotic family members can heterodimerize with pro-apoptotic family members and antagonize their function, thus protecting against death. In cells protected from death by overexpression of Bcl-2 much of the Bax is present in Bax:Bcl-2 hetero-multimers and its death signal is blocked as it cannot homodimerize. This led us to use the Bcl-2/Bax heterodimer as a target for new compounds which may provide a therapy particularly suited to tumour cells for which resistance to conventional therapy is associated with elevated expression of Bcl-2. We assessed whether apoptosis could be induced in prostate tumour cells by blocking this heterodimerization with synthetic peptide sequences derived from the BH3 domain of pro-apoptotic Bcl-2 family members. Prostate cells were found to undergo up to 40% apoptosis 48 h following the introduction of synthetic peptides from the BH3 domains of Bax and Bak. The caspase inhibitor z-VAD.fmk provided protection against apoptosis mediated by these peptides. Immunoprecipitation studies revealed that introduction of peptides derived from the BH3 regions of Bak and Pax into cells blocked Bak/Bcl-2 heterodimerization. These data suggest that by blocking the dimerization through which Bcl-2 would normally inhibit apoptosis the apoptotic pathway driven by Bak was re-opened. (C) 2001 Cancer Research Campaign http://www.bjcancer.com.
Grant Details