Alan E. Friedman, Ph.D.

The evaluation of biomarkers as diagnostic indicators for disease progression is an endeavor of intense academic and clinical research. Our group is interested in the regulation of cancer progression, which we are studying through a novel in vitro cell model system. This model, called the Prostatic Human Epithelial Cancer (PHEC) system, represents all three states of human prostate cancer progression: non-tumorigenic, tumorigenic and metastatic cells. For each state, we have individual cell lines in culture, and thus we are able to compare the three states directly, as they are generated from the same progenitor line. This allows us to study changes in expressed protein identities, concentrations, biomolecular interaction partners, and even genetic expression profiles, to understand the sub-cellular basis for prostate cancer progression.

Our research focuses on the identification of aberrant proteins and subtle changes in concentration in response to cellular changes, using mass spectrometry and other cutting edge protein chemistry tools. With these tools, we recently defined the behavior of one such protein, nucleoside diphosphate kinase A, or non-metastatic 23 H1 form (NM23-H1). Doing a comparative analysis of this protein in our PHEC cell lines, we discovered that NM23-H1 has a consistent regression in tumorigenic and metastatic states of cancer compared to its levels in the non-tumorigenic state, as illustrated by immunochemistry in Figure 1. This protein is the only known human histidine kinase, and may serve as the entry point for a two-component signal transduction (2CST), a style of protein regulation that is common in prokaryotes but seldom seen in eukaryotes above yeast. 2CST systems rely upon a histidine kinase for autophosphorylation, followed by the transfer of the phosphate group to a response regulator (RR), usually on an aspartic acid residue. The proposal of the role of NM23-H1 in such a 2CST system is outlined in Scheme 1. This is a new paradigm for the regulation of proteins in humans, and our laboratory is working to provide further evidence for the existence of the 2CST system in humans and to characterize its role in the progression of prostate cancer and its metastasis outside the prostate.