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 1

In LNCaP cells, phosphorylated PXN is a nuclear protein that regulates AR-mediated transcription.

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In LNCaP cells, phosphorylated PXN is a nuclear protein that regulates A...
(A) PS-PXN localizes to the nucleus. Immunofluorescence of PXN and PS-PXN with medium or DHT (25 nM) treatment (30 minutes). For all immunofluorescence, adjacent Hoechst staining represents the nucleus; experiments were repeated more than 3 times with identical results. Original magnification, ×40. (B) DHT stimulation of the PSA promoter requires PXN. Nsp or PXN siRNA–treated cells were transfected with PSA-luciferase and cytomegalovirus–β-gal plasmid; this was followed by DHT treatment (25 nM; 24 hours). PXN-knockdown cells were transfected with plasmids encoding WT PXN or PXN(S→A). Luciferase activity was normalized to β-gal and represented as fold increase over medium (n = 4). (C) PXN regulates expression of multiple androgen targets. Relative expression of DHT-induced PSA, FKBP5, NKX3-1, and c-FOS mRNAs in Nsp or siRNA-mediated PXN knockdown LNCaP cells. Data are represented as mean ± SEM (n = 3). *P ≤ 0.001; **P ≤ 0.05 relative to Nsp siRNA.