Oncotarget

Research Papers:

Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase

Jelani C. Zarif _, Laura E. Lamb, Veronique S. Schulz, Eric A. Nollet and Cindy K. Miranti

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Oncotarget. 2015; 6:6862-6876. https://doi.org/10.18632/oncotarget.3119

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Abstract

Jelani C. Zarif1,2, Laura E. Lamb3, Veronique V. Schulz1, Eric A. Nollet1,4, Cindy K. Miranti1

1Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503, USA

2Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA

3Department of Urology, Beaumont Health System - Research Institute, Royal Oak, MI 48073, USA

4Van Andel Institute Graduate School, Grand Rapids, MI 49503, USA

Correspondence to:

Cindy K. Miranti, e-mail: cindy.miranti@vai.org

Keywords: prostate cancer, nongenomic AR signaling, Src, metastasis, castration-resistant

Received: July 09, 2014     Accepted: January 08, 2015     Published: January 29, 2015

ABSTRACT

Castration-resistant prostate cancers still depend on nuclear androgen receptor (AR) function despite their lack of dependence on exogenous androgen. Second generation anti-androgen therapies are more efficient at blocking nuclear AR; however resistant tumors still develop. Recent studies indicate Src is highly active in these resistant tumors. By manipulating AR activity in several different prostate cancer cell lines through RNAi, drug treatment, and the use of a nuclear-deficient AR mutant, we demonstrate that androgen acting on cytoplasmic AR rapidly stimulates Src tyrosine kinase via a non-genomic mechanism. Cytoplasmic AR, acting through Src enhances laminin integrin-dependent invasion. Active Matriptase, which cleaves laminin, is elevated within minutes after androgen stimulation, and is subsequently shed into the medium. Matriptase activation and shedding induced by cytoplasmic AR is dependent on Src. Concomitantly, CDCP1/gp140, a Matriptase and Src substrate that controls integrin-based migration, is activated. However, only inhibition of Matriptase, but not CDCP1, suppresses the AR/Src-dependent increase in invasion. Matriptase, present in conditioned medium from AR-stimulated cells, is sufficient to enhance invasion in the absence of androgen. Thus, invasion is stimulated by a rapid but sustained increase in Src activity, mediated non-genomically by cytoplasmic AR, leading to rapid activation and shedding of the laminin protease Matriptase.


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