A Peptide Mimicking a Region in Proliferating Cell Nuclear Antigen Specific to Key Protein Interactions Is Cytotoxic to Breast Cancer
Autor: | Kelsey Dillehay, Yun-Ru Chen, Robert J. Hickey, Long Gu, Elizabeth A. Phipps, Gregg B. Fields, Lacey E. Dobrolecki, Zhongyun Dong, Shanna J Smith, Pattie Gulley, Karla S. Mabrey, Linda H. Malkas, David K. Ann |
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Rok vydání: | 2014 |
Předmět: |
Breast Neoplasms
Peptide Mice SCID Biology Protein Structure Secondary Random Allocation Mice Inbred NOD Proliferating Cell Nuclear Antigen Animals Humans Cytotoxic T cell Cytotoxicity Peptide sequence Mice Knockout Pharmacology chemistry.chemical_classification Cytotoxins Molecular Mimicry DNA replication Articles Molecular biology Peptide Fragments Protein Structure Tertiary Chromatin Cell biology Proliferating cell nuclear antigen chemistry Cancer cell MCF-7 Cells biology.protein Molecular Medicine Female Rabbits Protein Binding |
Zdroj: | Molecular Pharmacology. 87:263-276 |
ISSN: | 1521-0111 0026-895X |
Popis: | Proliferating cell nuclear antigen (PCNA) is a highly conserved protein necessary for proper component loading during the DNA replication and repair process. Proteins make a connection within the interdomain connector loop of PCNA, and much of the regulation is a result of the inherent competition for this docking site. If this target region of PCNA is modified, the DNA replication and repair process in cancer cells is potentially altered. Exploitation of this cancer-associated region has implications for targeted breast cancer therapy. In the present communication, we characterize a novel peptide (caPeptide) that has been synthesized to mimic the sequence identified as critical to the cancer-associated isoform of PCNA. This peptide is delivered into cells using a nine-arginine linking mechanism, and the resulting peptide (R9-cc-caPeptide) exhibits cytotoxicity in a triple-negative breast cancer cell line, MDA-MB-436, while having less of an effect on the normal counterparts (MCF10A and primary breast epithelial cells). The novel peptide was then evaluated for cytotoxicity using various in vivo techniques, including ATP activity assays, flow cytometry, and clonogenetic assays. This cytotoxicity has been observed in other breast cancer cell lines (MCF7 and HCC1937) and other forms of cancer (pancreatic and lymphoma). R9-cc-caPeptide has also been shown to block the association of PCNA with chromatin. Alanine scanning of the peptide sequence, combined with preliminary in silico modeling, gives insight to the disruptive ability and the molecular mechanism of action of the therapeutic peptide in vivo. |
Databáze: | OpenAIRE |
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