Amphipathic tail-anchoring peptide and Bcl-2 homology domain-3 (BH3) peptides from Bcl-2 family proteins induce apoptosis through different mechanisms.

Abstract

Bcl-2 homology domain-3 (BH3) peptides are potent cancer therapeutic reagents that target regulators of apoptotic cell death in cancer cells. However, their cytotoxic effects are affected by different expression levels of Bcl-2 family proteins. We recently found that the amphipathic tail-anchoring peptide (ATAP) from Bfl-1, a bifunctional Bcl-2 family member, produced strong pro-apoptotic activity by permeabilizing the mitochondrial outer membrane. Here, we test whether the activity of ATAP requires other cellular factors and whether ATAP has an advantage over the BH3 peptides in targeting cancer cells. Confocal microscopic imaging illustrates specific targeting of ATAP to mitochondria, whereas BH3 peptides show diffuse patterns of cytosolic distribution. Although the pro-apoptotic activities of BH3 peptides are largely inhibited by either overexpression of anti-apoptotic Bcl-2 or Bcl-xL or nullification of pro-apoptotic Bax and Bak in cells, the pro-apoptotic function of ATAP is not affected by these cellular factors. Reconstitution of synthetic ATAP into liposomal membranes results in release of fluorescent molecules of the size of cytochrome c from the liposomes, suggesting that the membrane permeabilizing activity of ATAP does not require additional protein factors. Because ATAP can target to the mitochondrial membrane and its pro-apoptotic activity does not depend on the content of Bcl-2 family proteins, it represents a promising candidate for anti-cancer drugs that can potentially overcome the intrinsic apoptosis-resistant nature of cancer cells.

• Authors: Jae-Kyun Ko, Kyoung-Han Choi, Jun Peng, Feng He, Zhi Zhang, Noah Weisleder, Jialing Lin, Jianjie Ma
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 11 Pg. 9038-48 (Mar 18 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21189256 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• BCL2-related protein A1
• BCL2L1 protein, human
• Bax protein (53-86)
• Liposomes
• Minor Histocompatibility Antigens
• Peptide Fragments
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• bcl-X Protein
• Cytochromes c

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cytochromes c (metabolism)
• HeLa Cells
• Humans
• Liposomes (chemistry)
• Minor Histocompatibility Antigens
• Mitochondrial Membranes (metabolism)
• Neoplasms (drug therapy, metabolism)
• Peptide Fragments (pharmacology)
• Permeability (drug effects)
• Proto-Oncogene Proteins (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (pharmacology)
• bcl-X Protein (metabolism)