ABSTRACT
The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle ('Cell Cycle Common'), versus those that were specifically enriched in a subset of cell cycle phases ('Phase Restricted'). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide desaturase 1 was identified as an AR-regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.
Subject(s)
Cell Cycle , Neoplasms/metabolism , Neoplasms/pathology , Receptors, Androgen/metabolism , Androgens/metabolism , Androgens/pharmacology , Base Sequence , Binding Sites , Cell Cycle/genetics , Cluster Analysis , Computational Biology/methods , Disease Progression , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Models, Biological , Neoplasms/genetics , Neoplasms/mortality , Nucleotide Motifs , Phenotype , Prognosis , Protein BindingABSTRACT
The cyclin/cyclin-dependent kinase (CDK)/retinoblastoma (RB)-axis is a critical modulator of cell cycle entry and is aberrant in many human cancers. New nodes of therapeutic intervention are needed that can delay or combat the onset of malignancies. The antitumor properties and mechanistic functions of PD-0332991 (PD; a potent and selective CDK4/6 inhibitor) were investigated using human prostate cancer (PCa) models and primary tumors. PD significantly impaired the capacity of PCa cells to proliferate by promoting a robust G1-arrest. Accordingly, key regulators of the G1-S cell cycle transition were modulated including G1 cyclins D, E and A. Subsequent investigation demonstrated the ability of PD to function in the presence of existing hormone-based regimens and to cooperate with ionizing radiation to further suppress cellular growth. Importantly, it was determined that PD is a critical mediator of PD action. The anti-proliferative impact of CDK4/6 inhibition was revealed through reduced proliferation and delayed growth using PCa cell xenografts. Finally, first-in-field effects of PD on proliferation were observed in primary human prostatectomy tumor tissue explants. This study shows that selective CDK4/6 inhibition, using PD either as a single-agent or in combination, hinders key proliferative pathways necessary for disease progression and that RB status is a critical prognostic determinant for therapeutic efficacy. Combined, these pre-clinical findings identify selective targeting of CDK4/6 as a bona fide therapeutic target in both early stage and advanced PCa and underscore the benefit of personalized medicine to enhance treatment response.
Subject(s)
Antineoplastic Agents/pharmacology , Molecular Targeted Therapy , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Receptors, Androgen/metabolism , Signal Transduction/drug effects , Animals , Antineoplastic Agents/therapeutic use , Cell Cycle/drug effects , Cell Cycle/radiation effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Feasibility Studies , Humans , Male , Mice , Piperazines/pharmacology , Piperazines/therapeutic use , Prostatic Neoplasms/metabolism , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Protein Kinase Inhibitors/therapeutic use , Pyridines/pharmacology , Pyridines/therapeutic use , Retinoblastoma/drug therapy , Retinoblastoma/pathology , Xenograft Model Antitumor AssaysSubject(s)
Intestinal Pseudo-Obstruction/diagnostic imaging , Adult , Chronic Disease , Humans , Male , RadiographyABSTRACT
The gene frequencies for human red cell glyoxalase I have been determined in 1,222 unrelated subjects from two areas of Central Italy (Rome and Viareggio). No significant difference has been found between the two samples. Therefore the data have been pooled. The cumulative GLO1 gene frequency estimate is 0.376 +/- 0.010. This gene frequency is comparable to that reported for another sample from Rome and very similar to that found in Naples while it is significantly lower than those reported for Northern Italy (Milan and Genoa) and for the Northern European Caucasian populations studied so far.
