Journal Article

Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation

Raj, Ganesh V., Melamed, Jonathan, Rossi, Randall, Deng, Fang-Ming, DeFranco, Donald B., Hammes, Stephen R., Kapur, Payel, De Castro, Ismary, Sen, Aritro

2012

Overview

In prostate cancer, the signals that drive cell proliferation change as tumors progress from castration-sensitive (androgen-dominant) to castration-resistant states. While the mechanisms underlying this change remain uncertain, characterization of common signaling components that regulate both stages of prostate cancer proliferation is important for developing effective treatment strategies. Here, we demonstrate that paxillin, a known cytoplasmic adaptor protein, regulates both androgen- and EGF-induced nuclear signaling. We show that androgen and EGF promoted MAPK-dependent phosphorylation of paxillin, resulting in nuclear translocation of paxillin. We found nuclear paxillin could then associate with androgen-stimulated androgen receptor (AR). This complex bound AR-sensitive promoters, retaining AR within the nucleus and regulating AR-mediated transcription. Nuclear paxillin also complexed with ERK and ELK1, mediating c-FOS and cyclin D1 expression; this was followed by proliferation. Thus, paxillin is a liaison between extranuclear MAPK signaling and nuclear transcription in response to androgens and growth factors, making it a potential regulator of both castration-sensitive and castration-resistant prostate cancer. Accordingly, paxillin was required for normal growth of human prostate cancer cell xenografts, and its expression was elevated in human prostate cancer tissue microarrays. Paxillin is therefore a potential biomarker for prostate cancer proliferation and a possible therapeutic target for prostate cancer treatment.

• Publisher: American Society for Clinical Investigation
• Subject: Active Transport, Cell Nucleus / Androgens / Animals / Antigens / Biomedical research / Cell growth / Cell Line, Tumor / Cell Nucleus - metabolism / Cell Proliferation / Cellular signal transduction / Dihydrotestosterone - pharmacology / ets-Domain Protein Elk-1 - metabolism / Extracellular Signal-Regulated MAP Kinases - metabolism / Female / Gene Expression Regulation / Genetic aspects / Granulosa Cells - metabolism / Growth factors / Health aspects / Homeodomain Proteins - genetics / Humans / Kinases / Male / MAP Kinase Signaling System / Mice / Mice, Inbred C57BL / Mice, Nude / Neoplasm Transplantation / Paxillin - genetics / Paxillin - metabolism / Phosphoproteins - metabolism / Phosphorylation / Promoter Regions, Genetic / Prostate cancer / Prostate-Specific Antigen - genetics / Prostate-Specific Antigen - metabolism / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Protein Binding / Proteins / Proto-Oncogene Proteins c-fos - genetics / Proto-Oncogene Proteins c-fos - metabolism / Receptors, Androgen - metabolism / Transcription Factors - genetics / Transcription, Genetic / Transcriptional Activation / Tumors