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Published on: October 5, 2012
Induction of apoptosis in prostate carcinoma cells by BH3 peptides which inhibit Bak/Bcl-2 interactions
N M Finnegan1, J F Curtin, G Prevost
1Dept of Biochemistry, University College Cork, Lee Maltings, Prospect Row, Cork, Ireland.
Abstract:
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 Bax 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.
Insights
Targeting Bcl-2/Bax protein interactions with BH3-derived peptides can induce apoptosis in prostate tumor cells. This approach re-opens the apoptotic pathway, offering a potential therapy for Bcl-2-resistant cancers.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Proteins of the Bcl-2 family regulate apoptosis through heterodimerization.
- Anti-apoptotic proteins like Bcl-2 inhibit cell death by binding to pro-apoptotic proteins (e.g., Bax, Bak).
- Elevated Bcl-2 expression in tumors can confer resistance to conventional therapies.
Purpose of the Study:
- To investigate if blocking Bcl-2/Bax heterodimerization can induce apoptosis in prostate tumor cells.
- To identify novel therapeutic strategies targeting Bcl-2-overexpressing resistant tumors.
Main Methods:
- Utilized synthetic peptides derived from the BH3 domain of pro-apoptotic proteins (Bax, Bak).
- Introduced peptides into prostate tumor cells and assessed apoptosis induction.
- Employed caspase inhibitor z-VAD.fmk to confirm caspase-dependent apoptosis.
- Conducted immunoprecipitation studies to verify disruption of Bak/Bcl-2 heterodimerization.
Main Results:
- Synthetic peptides from Bax and Bak BH3 domains induced up to 40% apoptosis in prostate cells within 48 hours.
- The caspase inhibitor z-VAD.fmk protected cells from peptide-induced apoptosis.
- Peptide introduction successfully blocked Bak/Bcl-2 heterodimerization, preventing Bcl-2 from inhibiting apoptosis.
Conclusions:
- Blocking Bcl-2/Bax heterodimerization effectively re-opens the apoptotic pathway mediated by Bak.
- Synthetic BH3-derived peptides show promise as a therapeutic strategy against prostate tumors with elevated Bcl-2 expression and therapy resistance.
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