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Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase.
Oncotarget 2015; 6(9):6862-76O

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.

Authors+Show Affiliations

Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA.Department of Urology, Beaumont Health System - Research Institute, Royal Oak, MI 48073, USA.Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503, USA.Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Van Andel Institute Graduate School, Grand Rapids, MI 49503, USA.Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25730905

Citation

Zarif, Jelani C., et al. "Androgen Receptor Non-nuclear Regulation of Prostate Cancer Cell Invasion Mediated By Src and Matriptase." Oncotarget, vol. 6, no. 9, 2015, pp. 6862-76.
Zarif JC, Lamb LE, Schulz VV, et al. Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase. Oncotarget. 2015;6(9):6862-76.
Zarif, J. C., Lamb, L. E., Schulz, V. V., Nollet, E. A., & Miranti, C. K. (2015). Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase. Oncotarget, 6(9), pp. 6862-76.
Zarif JC, et al. Androgen Receptor Non-nuclear Regulation of Prostate Cancer Cell Invasion Mediated By Src and Matriptase. Oncotarget. 2015 Mar 30;6(9):6862-76. PubMed PMID: 25730905.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase. AU - Zarif,Jelani C, AU - Lamb,Laura E, AU - Schulz,Veronique V, AU - Nollet,Eric A, AU - Miranti,Cindy K, PY - 2014/07/09/received PY - 2015/01/08/accepted PY - 2015/3/3/entrez PY - 2015/3/3/pubmed PY - 2016/1/16/medline KW - Src KW - castration-resistant KW - metastasis KW - nongenomic AR signaling KW - prostate cancer SP - 6862 EP - 76 JF - Oncotarget JO - Oncotarget VL - 6 IS - 9 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/25730905/Androgen_receptor_non_nuclear_regulation_of_prostate_cancer_cell_invasion_mediated_by_Src_and_matriptase_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=3119 DB - PRIME DP - Unbound Medicine ER -