CaPeptides: Selectively targeting caPCNA and sensitizing gemcitabine in pancreatic cancer cells

Abstract

Abstract caPeptides that block the functions of caPCNA, cancer associated proliferating cell nuclear antigen in malignant cells has been developed by our laboratory and showed promising anti-cancer therapeutic activities. Previously, we have identified caPCNA, an acidic isoform of PCNA that presents in various cancer cells and appears to be associated, at least in part, with malignant transformation of cells. Since 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 the inhibition of DNA replication in cancer cells. The investigation of the interaction of caPCNA with its binding partners including flap structure-specific endonuclease 1(Fen-1) and xeroderma pimentosum complementation group G (XPG) has led us to identify an amino acid domain sequence that confers the cancer cell specificity of caPCNA. We synthesized caPeptides, small caPCNA related peptides derived from this sequence to 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 caPeptides to be cytotoxic by themselves or in combination with cancer chemotherapeutic drugs. Our results demonstrated that these peptides were cytotoxic to pancreatic cancer cells and more significantly they rendered resistant pancreatic cells to be 10-fold more sensitive to gemcitabine, a standard clinical chemotherapeutic agent for treating pancreatic cancer patients. Considering that pancreatic cancer is well known for its high mortality rate due to its chemotherapy ineffectiveness and resistances to gemcitabine our studies render further investigations on the anti-neoplastic action and mechanisms of the peptides in pancreatic cancer.