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 7

PXN knockdown inhibits prostate cancer growth and tumor development, and PXN expression is upregulated in prostate cancer patient samples.

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PXN knockdown inhibits prostate cancer growth and tumor development, and...
(A–D) PXN knockdown in PC3 cells suppresses tumor formation in xenografts. Nude mice (n = 15/group) were injected subcutaneously with 0.2 ml (1.5 × 106) PC3 cells infected with PXN shRNA or GFP shRNA-negative control. (A) The growth curve of tumors bearing PC3 cell xenografts. (B) The tumor weights of prostate cancer cell xenografts. *P ≤ 0.005 comparing PXN shRNA and GFP shRNA. (C and D) ELK1 phosphorylation and cyclin D1 expression are lower in xenograft tumors lacking PXN. Protein levels of PXN, p-ELK1, and t-ELK1 (C) as well as mRNA levels of cyclin D1 (D) in excised tumors that were treated with GFP or PXN shRNA. (E and F) PXN levels and downstream effectors are upregulated in prostate cancer TMAs. TMA sections were subjected to immunohistochemistry and PXN, AR, cyclin D1, and Ki67 expression measured by scoring intensity and cell number. (E) Data represented as percentage of maximum score for AR, PXN, and cyclin D1 and as percentage of positive cells for Ki67. *P ≤ 0.0001; **P ≤ 0.001 relative to control or BPH samples. All data are represented as mean ± SEM (n = 15). (F) Representative TMA sections showing PXN, cyclin D1, and AR expression in normal/BPH and cancer samples and PS-PXN expression in cancer samples (note that PS-PXN expression was not statistically different in benign versus cancerous prostate).