Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation
Aritro Sen, … , Randall Rossi, Stephen R. Hammes
Aritro Sen, … , Randall Rossi, Stephen R. Hammes
Published June 11, 2012
Citation Information: J Clin Invest. 2012;122(7):2469-2481. https://doi.org/10.1172/JCI62044.
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Research Article Oncology

Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation

Abstract

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.

Authors

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

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Figure 4

PXN specifically regulates AR nuclear localization in primary GCs.

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PXN specifically regulates AR nuclear localization in primary GCs. Prima...
Primary GCs from C57BL/6J mouse ovaries were treated with DHT or estradiol (25 nM) for 30 minutes. (A) Immunofluorescence studies (n = 3 experiments with identical results) showed that, under basal conditions (medium), PXN is predominantly cytoplasmic. Under DHT or estradiol (E2) stimulation, PS-PXN is primarily nuclear. Adjacent Hoechst staining represents the nucleus. (B and C) Immunofluorescence studies (n = 3 experiments with identical results) of primary GCs treated with Nsp or PXN-specific siRNA. PXN ablation prevents DHT-induced nuclear translocation of AR (B), but has no effect on nuclear localization of ERα in medium or estradiol-treated cells (C). (D) Immunofluorescence studies (n = 3 experiments with identical results) in MCF7 breast cancer cells showing siRNA-mediated knockdown of PXN has no effect on ERα nuclear localization in medium or estradiol-treated cells. Original magnification, ×40. (E) PXN is not required for ERE-mediated transcription. Nsp or PXN-specific siRNA treated MCF7 cells were transiently transfected with ERE reporter luciferase construct plus cytomegalovirus–β-gal plasmid. ERE-luciferase activity was normalized to β-gal expression and data represented as fold increase with respect to medium treatment (mean ± SEM, n = 3). *P ≤ 0.001 relative to medium. The blot on the right shows PXN knockdown.