PT  - JOURNAL ARTICLE
AU  - Shanna J Smith
AU  - Long Gu
AU  - Elizabeth A Phipps
AU  - Lacey E Dobrolecki
AU  - Karla S Mabrey
AU  - Pattie Gulley
AU  - Kelsey L Dillehay
AU  - Zhongyun Dong
AU  - Gregg B Fields
AU  - Yun-Ru Chen
AU  - David Ann
AU  - Robert J Hickey
AU  - Linda H Malkas
TI  - A Peptide Mimicking a Region in Proliferating Cell Nuclear Antigen (PCNA) Specific to Key Protein Interactions is Cytotoxic to Breast Cancer
AID  - 10.1124/mol.114.093211
DP  - 2014 Jan 01
TA  - Molecular Pharmacology
PG  - mol.114.093211
4099  - http://molpharm.aspetjournals.org/content/early/2014/12/05/mol.114.093211.short
4100  - http://molpharm.aspetjournals.org/content/early/2014/12/05/mol.114.093211.full
AB  - 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 (IDCL) 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 in targeted breast cancer therapy. In the present communication, we characterize a novel peptide (caPeptide) that has been synthesized to mimick the sequence identified as critical to the cancer-associated isoform of PCNA (caPCNA). 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 (MCF 7 and HCC 1937), and other forms of cancer (pancreatic and lymphoma). R9-cc-caPeptide has also been shown to block the association of PCNA association 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.