Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase.
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.
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.
Jelani C
JC
Zarif
Department of Urology, Beaumont Health System - Research Institute, Royal Oak, MI 48073, USA.
Laura E
LE
Lamb
Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Veronique V
VV
Schulz
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.
Eric A
EA
Nollet
Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Cindy K
CK
Miranti
D000728:Androgens / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D048430:Cell Shape; D017077:Culture Media, Conditioned / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039121:Integrin alpha6beta1 / Q000378:metabolism; D007797:Laminin / Q000737:chemistry; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D019061:src-Family Kinases / Q000378:metabolism*
C410798:AR protein, human; D000728:Androgens; D017077:Culture Media, Conditioned; D039121:Integrin alpha6beta1; D007797:Laminin; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D019061:src-Family Kinases; D012697:Serine Endopeptidases; C485596:ST14 protein, human
Src; castration-resistant; metastasis; nongenomic AR signaling; prostate cancer