A peptide fragment of azurin induces a p53-mediated cell cycle arrest in human breast cancer cells.

Abstract

We report that amino acids 50 to 77 of azurin (p28) preferentially enter the human breast cancer cell lines MCF-7, ZR-75-1, and T47D through a caveolin-mediated pathway. Although p28 enters p53 wild-type MCF-7 and the isogenic p53 dominant-negative MDD2 breast cancer cell lines, p28 only induces a G(2)-M-phase cell cycle arrest and apoptosis in MCF-7 cells. p28 exerts its antiproliferative activity by reducing proteasomal degradation of p53 through formation of a p28:p53 complex within a hydrophobic DNA-binding domain (amino acids 80-276), increasing p53 levels and DNA-binding activity. Subsequent elevation of the cyclin-dependent kinase inhibitors p21 and p27 reduces cyclin-dependent kinase 2 and cyclin A levels in a time-dependent manner in MCF-7 cells but not in MDD2 cells. These results suggest that p28 and similar peptides that significantly reduce proteasomal degradation of p53 by a MDM2-independent pathway(s) may provide a unique series of cytostatic and cytotoxic (apoptotic) chemotherapeutic agents.

• Authors: Tohru Yamada, Rajeshwari R Mehta, Fatima Lekmine, Konstantin Christov, Marissa L King, Dibyen Majumdar, Anne Shilkaitis, Albert Green, Laura Bratescu, Craig W Beattie, Tapas K Das Gupta
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 10 Pg. 2947-58 (Oct 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19808975 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Cyclins
• Peptide Fragments
• Tumor Suppressor Protein p53
• Azurin
• Proteasome Endopeptidase Complex
• Bromodeoxyuridine

Topics

• Animals
• Azurin (chemistry)
• Breast Neoplasms (pathology)
• Bromodeoxyuridine (metabolism)
• Cell Cycle (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclins (metabolism)
• Female
• Humans
• Mice
• Peptide Fragments (pharmacology)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Binding (drug effects)
• Protein Processing, Post-Translational (drug effects)
• Protein Stability (drug effects)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays