My laboratory has focused on elucidating the mechanisms underlying cancer cell DNA damage accumulation, which has also been correlated with disease progression. Our laboratory was the first to successfully isolate an intact multiprotein DNA synthesis complex that is both stable and fully functional, (termed the DNA synthesome), from a variety of mammalian cell lines and tissues. Subsequent work demonstrated that the synthesome of malignant epithelial cells has a significantly decreased DNA synthesis fidelity, (exhibiting a more error-prone synthesis process), than the complex of non-malignant epithelial cells. We demonstrated that this occurs in intact epithelial cells as well. We also showed that non-malignant human cell transformation to a malignant state is accompanied by an alteration of a specific protein component of the synthesome, namely proliferating cell nuclear antigen (PCNA). Different isoforms of PCNA that display both acidic and basic isoelectric points (pI) have been demonstrated. These analyses also revealed that an additional acidic form of PCNA was highly expressed in cancer cells (referred to as the cancer-associated PCNA or caPCNA). An antibody was developed to caPCNA that proved to be highly selective for this isoform in cancer cells.
In the course of our studies we have identified a small caPCNA related peptide (caPeptide), as well as small molecule compounds targeting caPCNA, that promote cancer cell cytotoxicity with great specificity. These agents have the potential ability to block the binding of several cellular proteins that participate in DNA replication, repair, cell cycle control, transcription, and chromosomal recombination in cancer cells. The binding of full length caPCNA to the proteins mediating these processes is disrupted when the caPeptide or small molecule compounds are allowed to compete with these proteins for their naturally occurring binding site on caPCNA. This disruption in the function of vital cellular processes would render caPeptide or small molecule compounds cytotoxic by themselves, or in combination with other agents, such as, DNA damaging cancer chemotherapeutic drugs. These agents, either alone or in combination with other cancer therapy agents are potentially useful cancer chemotherapeutics or augmentors of the pharmacodynamic effect of specific anti-cancer chemotherapeutics.
February 02, 2015
November 22, 2014
October 27, 2014