Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation

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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58 Scopus citations

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 ARmediated 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.

Original languageEnglish (US)
Pages (from-to)2469-2481
Number of pages13
JournalJournal of Clinical Investigation
Volume122
Issue number7
DOIs
StatePublished - Jul 2 2012

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ASJC Scopus subject areas

  • Medicine(all)

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Sen, A., De Castro, I., DeFranco, D. B., Deng, F. M., Melamed, J., Kapur, P., Raj, G. V., Rossi, R., & Hammes, S. R. (2012). Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation. Journal of Clinical Investigation, 122(7), 2469-2481. https://doi.org/10.1172/JCI62044