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 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. IntroductionProstate cancer is associated with significant morbidity and mortality and is the second most common cancer among men worldwide. One feature of prostate cancer progression is its apparent change in androgen responsiveness over time. At diagnosis, locally advanced prostate cancers are treated successfully by prostatectomy, irradiation, and/or anti-androgen therapy, suggesting that tumor cells are dependent on androgens for continued growth and survival. In contrast, despite treatment, many advanced tumors enter a more aggressive castration-resistant state after 18-24 months. This observation suggests fundamental changes in the extracellular triggers and intracellular signaling pathways that regulate proliferation and cell migration (1-3) in aggressive tumors. The reasons for this dramatic transformation in phenotype are not well understood. However, several likely interconnected mechanisms of castration resistance have been proposed. For example, alterations in intraprostatic androgen production or metabolism ("intracrine" androgen production) in castration-resistant prostate cancer (4, 5) could lead to elevated local androgen concentrations in the setting of low serum androgen levels. Alternatively, the abundance or activity of androgen receptors (ARs) and their various transcriptional coregulators might be modified in castration-resistant prostate cancer cells so that they respond to lower concentrations of androgen or other steroids (6). Finally, prostate cancer cells might ad...

Paxillin controls endothelial cell migration and tumor angiogenesis by altering neuropilin 2 expression

“…The VEGF-phosphorylated transcription factor ELK1 (Murata et al, 2000) also can bind to the NRP2 promoter region. ELK1 has been reported to form a complex with nuclear paxillin to regulate cell functions (Sen et al, 2012), and so paxillin could control NRP2 transcriptional activity through ELK1 in capillary endothelial cells. It is as yet unknown whether paxillin controls the expression of receptors for other angiogenic factors besides NRP2.…”

“…This seems to be controversial because paxillin expression has also been reported to be elevated in lung, prostate, breast, cervical and other tumors (Deakin et al, 2012;Jagadeeswaran et al, 2008;Mackinnon et al, 2011;Salgia et al, 1999;Sen et al, 2012). These conflicting results might be because these studies did not address the specific expression of paxillin in tumor endothelial cells because different cell components of cancers (e.g.…”

“…Paxillin-knockout mice are embryonic lethal because of developmental defects in the mesoderm (Hagel et al, 2002), and paxillin knockdown causes defects in embryonic stem cell spreading (Wade et al, 2002) and enhances HeLa cell migration (Yano et al, 2004). Interestingly, paxillin mutations and changes in protein expression are also associated with alterations in the malignant progression of many tumors (Deakin et al, 2012), including breast (Madan et al, 2006;Short et al, 2007), lung (Jagadeeswaran et al, 2008;Mackinnon et al, 2011;Salgia et al, 1999), prostate (Sen et al, 2012), melanoma (Velasco-Velázquez et al, 2008) and colorectal cancer (Yang et al, 2010).…”

Androgen actions in the ovary: balance is key

“…2). Recently (Sen et al , 2012(Sen et al , 2014, it has been found that androgens can promote Erk signaling via matrixmetaloproteinases (MMPs)-mediated trans-activation of the epidermal growth factor receptor (EGFR), a mechanism that is conserved from Xenopus (Rasar et al 2006) to mice (Carbajal et al 2011) and humans (Evaul & Hammes 2008). These observations have given rise to the interesting concept that, outside the nucleus, androgen actions are very similar to those of growth factors.…”

“…These observations have given rise to the interesting concept that, outside the nucleus, androgen actions are very similar to those of growth factors. Intriguingly, a multi-domain adaptor protein, called paxillin (PXN), traditionally thought to regulate cytoskeletal remodeling and focal adhesion functions, is an essential mediator of androgen-induced Erk activation (Sen et al , 2012(Sen et al , 2014. Furthermore, PXN serves as a liaison between extranuclear signaling and nuclear transcription in response to androgens (Sen et al 2012).…”