Abstract 1597: Expression of caPCNA and antineoplastic action of caPeptides in pancreatic cancer cells

Abstract

Abstract Our laboratory previously reported the identification of an acidic isoform of proliferating cell nuclear antigen (caPCNA) in various cancer cells, which appears to be associated, at least in part, with malignant transformation of cells. The current studies show the expression of caPCNA in BXPC-3, Paca-2 and Capan-1 pancreatic cancer cells. Since Proliferating Cell Nuclear Antigen (PCNA) is involved in DNA replication and repair in prokaryote and eukaryote cells, we hypothesize that caPCNA is likely to perform similar functions specifically in cancer cells. Antibodies developed against caPCNA showed growth inhibition activity in cancer cells suggesting caPCNA is related to the proliferation of malignant cells. In order to begin to understand the function of caPCNA in cellular malignant transformation, we have investigated the interaction of caPCNA with its binding partners including flap structure-specific endonuclease 1(Fen-1) and xeroderma pimentosum complementation group G (XPG). We have identified an amino acid domain sequence that confers the cancer cell specificity of caPCNA. In the course of our studies we synthesized small caPCNA related peptides (caPeptides) derived from this sequence that promote cancer cell cytotoxicity. caPeptides have the potential ability to compete with several cellular proteins that participate in DNA replication, repair, cell cycle control, transcription, and chromosomal recombination for their naturally occurring binding site on caPCNA and block binding of full length caPCNA to these proteins. The disruption of the interaction between caPCNA and its binding proteins prevents cancer cellular functions (vital cellular machinery) that recruit caPCNA and therefore may lead caPCNA-derived peptides to be cytotoxic by themselves or in combination with cancer chemotherapeutic drugs. These peptides, either alone or in combination with other anticancer agents are potentially useful cancer chemotherapeutics or augmentors of the pharmacodynamic effect of specific anti-cancer chemotherapeutics. Our results show that these peptides demonstrate promising growth inhibition and cytotoxicity in pancreatic cancer cells. Considering that pancreatic cancer is well known for its high mortality rate due to its chemotherapy ineffectiveness our studies render further investigations on the action of caPCNA and the anti-neoplastic mechanism of the peptides in pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1597.