Abstract 3801: Androgen Receptor non-genomic regulation of prostate tumor cell invasion and metastasis through Src signaling and Matriptase .

Abstract

Abstract Prostate cancer is the leading cause of cancer deaths in men here in the U.S. and over 240,000 new cases are predicted to be diagnosed this year. Initially, tumors arising in this gland rely on the androgen receptor (AR) and its ligand, dihydrotestosterone (DHT) for growth and survival. At this stage, androgen deprivation therapy (ADT) can lead to tumor regression. Unfortunately, patients typically relapse within two to three years and tumors no longer respond to ADT; this stage is termed castration-resistant prostate cancer (CRPC) for which there is no cure. At this stage, AR expression is either increased or mutationally activated and non-responsive to physiological levels of androgen. Several reports have shown that AR has both genomic signaling within nucleus and non-genomic signaling within the cytoplasm. Using prostate tumor cell line PC-3, expressing wild-type AR (PC3-AR), we reported that AR genomic signaling leads to an increase in integrin α6β1 transcription and expression, which in turn increases Bcl-xL expression, a mechanism that regulates prostate cancer cell survival. However, a role for AR and integrin α6β1 in prostate cancer metastasis has not been examined. In addition to promoting cell survival, integrins are critically important for cell movement and can activate Src. We observed that in the absence of androgen, PC3-AR cells have increased Src activity as well as enhanced cell migration and invasion relative to cells that do not expressing AR. Androgen responsive prostate cancer cell lines LNCaP, VCaP and C42 which express AR endogenously, have enhanced invasion and Src activity once stimulated with androgen. We found that knock-down of AR decreased Src activity in PC3-AR cells, as well as in LNCaP and C42 cells. We also found that inhibiting the expression of either AR or Src blocked the ability of cells to invade through matrix in vitro. However, neither AR nor Src possess the ability to degrade ECM proteins. Thus, we hypothesize that AR activates Src in a non-genomic fashion to promote a metastatic phenotype by the regulation of a downstream protease. To test our hypothesis, we set out to determine how AR/Src signaling controls the expression and/or activity of a protease that can degrade proteins in the ECM to promote metastasis. Our data shows that the protease downstream of AR/Src signaling is matriptase, a transmembrane serine protease that has been recently reported to cleave laminin. We observe matriptase cellular expression levels decrease in androgen responsive cell lines once stimulated with androgen as early as twenty minutes. This is suggestive that this is regulated through a non-genomic signaling mechanism. Also seen in these androgen stimulated cells within twenty minutes is that matriptase is shed and found within the media at higher levels relative to the media of non-stimulated cells. Citation Format: Jelani C. Zarif, Laura E. Lamb, Cindy K. Miranti. Androgen Receptor non-genomic regulation of prostate tumor cell invasion and metastasis through Src signaling and Matriptase . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3801. doi:10.1158/1538-7445.AM2013-3801