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 8

PXN mediates extranuclear and nuclear AR and ERK signaling.

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PXN mediates extranuclear and nuclear AR and ERK signaling. Androgen bin...
Androgen binds ARs at or near the plasma membrane, which transactivates the EGFR via MMP-mediated release of EGFR ligands. EGFR can also be activated directly by EGF. This activates Src, which phosphorylates PXN on tyrosine residues, enabling Raf to activate MEK/ERK. ERK then mediates phosphorylation of PXN at serine residues (though not necessarily directly), and PS-PXN enters the nucleus. Meanwhile, androgen-bound AR also translocates to the nucleus. In the nucleus, PS-PXN interacts with androgen-bound AR to retain it in the nucleus. PS-PXN then associates with or near the AR on the PSA/NKX3-1 promoter to help promote AR-driven transcription (left). Activated ERK also enters the nucleus, where PS-PXN, p-ERK, and ELK1 form a complex and ERK phosphorylates ELK1, which induces c-FOS expression. The latter then activates cyclin D1 promoter activity/cyclin D1 expression (right), thereby promoting cell proliferation.