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

被引:39
作者
Zarif, Jelani C. [1 ,2 ]
Lamb, Laura E. [3 ]
Schulz, Veronique V. [1 ]
Nollet, Eric A. [1 ,4 ]
Miranti, Cindy K. [1 ]
机构
[1] Van Andel Res Inst, Lab Integrin Signaling & Tumorigenesis, Grand Rapids, MI 49503 USA
[2] Michigan State Univ, Cell & Mol Biol Program, E Lansing, MI 48824 USA
[3] Beaumont Hlth Syst, Dept Urol, Res Inst, Royal Oak, MI 48073 USA
[4] Van Andel Inst Grad Sch, Grand Rapids, MI 49503 USA
基金
美国国家卫生研究院;
关键词
prostate cancer; nongenomic AR signaling; Src; metastasis; castration-resistant; DOMAIN-CONTAINING PROTEIN-1; PATHWAY ACTIVATION; SIGNALING PATHWAYS; NONGENOMIC ACTIONS; STEROID-HORMONES; FAMILY KINASES; GROWTH; ENZALUTAMIDE; PROGRESSION; RESISTANCE;
D O I
10.18632/oncotarget.3119
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:6862 / 6876
页数:15
相关论文
共 55 条
  • [1] Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression
    Agoulnik, IU
    Vaid, A
    Bingman, WE
    Erdeme, H
    Frolov, A
    Smith, CL
    Ayala, G
    Ittmann, MM
    Weigel, NL
    [J]. CANCER RESEARCH, 2005, 65 (17) : 7959 - 7967
  • [2] DU-145 and PC-3 human prostate cancer cell lines express androgen receptor: Implications for the androgen receptor functions and regulation
    Alimirah, F
    Chen, JM
    Basrawala, Z
    Xin, H
    Choubey, D
    [J]. FEBS LETTERS, 2006, 580 (09): : 2294 - 2300
  • [3] The role of membrane microdomains in transmembrane signaling through the epithelial glycoprotein Gp140/CDCP1
    Alvares, Stacy M.
    Dunn, Clarence A.
    Brown, Tod A.
    Wayner, Elizabeth E.
    Carter, William G.
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 2008, 1780 (03): : 486 - 496
  • [4] Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault
    Arnold, JT
    Isaacs, JT
    [J]. ENDOCRINE-RELATED CANCER, 2002, 9 (01) : 61 - 73
  • [5] Src kinase potentiates androgen receptor transactivation function and invasion of androgen-independent prostate cancer C4-2 cells
    Asim, M.
    Siddiqui, I. A.
    Hafeez, B. B.
    Baniahmad, A.
    Mukhtar, H.
    [J]. ONCOGENE, 2008, 27 (25) : 3596 - 3604
  • [6] Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases
    Boonyaratanakornkit, V
    Scott, MP
    Ribon, V
    Sherman, L
    Anderson, SM
    Maller, JL
    Miller, WT
    Edwards, DP
    [J]. MOLECULAR CELL, 2001, 8 (02) : 269 - 280
  • [7] Invasive Prostate Carcinoma Driven by c-Src and Androgen Receptor Synergy
    Cai, Houjian
    Babic, Ivan
    Wei, Xiao
    Huang, Jiaoti
    Witte, Owen N.
    [J]. CANCER RESEARCH, 2011, 71 (03) : 862 - 872
  • [8] In vivo cleaved CDCP1 promotes early tumor dissemination via complexing with activated β1 integrin and induction of FAK/PI3K/Akt motility signaling
    Casar, B.
    Rimann, I.
    Kato, H.
    Shattil, S. J.
    Quigley, J. P.
    Deryugina, E. I.
    [J]. ONCOGENE, 2014, 33 (02) : 255 - 268
  • [9] Rapid signalling pathway activation by androgens in epithelial and stromal cells
    Castoria, G
    Lombardi, M
    Barone, MV
    Bilancio, A
    Di Domenico, M
    De Falco, A
    Varricchio, L
    Bottero, D
    Nanayakkara, M
    Migliaccio, A
    Auricchio, F
    [J]. STEROIDS, 2004, 69 (8-9) : 517 - 522
  • [10] Extranuclear Functions of ER Impact Invasive Migration and Metastasis by Breast Cancer Cells
    Chakravarty, Dimple
    Nair, Sujit S.
    Santhamma, Bindu
    Nair, Binoj C.
    Wang, Long
    Bandyopadhyay, Abhik
    Agyin, Joseph K.
    Brann, Darrell
    Sun, Lu-Zhe
    Yeh, I-Tien
    Lee, Francis Y.
    Tekmal, Rajeshwar Rao
    Kumar, Rakesh
    Vadlamudi, Ratna K.
    [J]. CANCER RESEARCH, 2010, 70 (10) : 4092 - 4101