In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 4_Supplement ( 2012-02-06), p. A5-A5
Abstract:
Prostate cancer is the leading cause of cancer deaths in U.S. men and an estimated 240,890 new cases will be diagnosed in 2011. Initially, the malignant tumors arising from this gland rely on the androgen receptor (AR) and its steroid hormone, dihydrotestosterone (DHT) for growth and survival. At this stage, androgen deprivation therapy (ADT) can lead to tumor regression. Unfortunately, patients typically relapse within two 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 either wildtype or mutated 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/or integrin α6β1 in prostate cancer metastasis has not been examined. In addition to their role in promoting cell survival, integrins are critically important for cell movement and can activate Src. We observed that in the absence of androgen, PC-3 cells expressing AR have increased Src activity as well as enhanced cell migration and invasion, by PC3-AR, relative to cell not expressing AR, when seeded on laminin to engage integrin α6β1. Thus, we hypothesize that AR-dependent stimulation of integrin α6β1 expression is required to activate Src and promote a metastatic phenotype. We found that knock-down of AR decreased Src activity in PC3-AR cells, as well as in LNCaP cells that retain endogenous AR expression. We also found that inhibiting the expression of either AR or Src blocked the ability of cells to invade in vitro. However, blocking integrin α6 expression did not significantly block cell invasion, nor did it suppress Src activity/expression. We subsequently found that suppression of integrin α6 caused a compensatory increase in another integrin, α3β1, such that depletion of both α6 and α3 integrins was required to suppress cell invasion. To elucidate the mechanism of AR-mediated Src activation, we generated prostate tumor cells that express AR mutants defective in Src binding (ARΔPro) and will compare them to mutants defective in AR-mediated transcription (ARΔNLS). We expect that the ARΔPro mutant will not associate with or activate Src, and there will be decreased tumor cell movement. To determine how Src activity increases invasiveness, we have investigated the role of AR and Src in controlling the expression and/or activity of proteases that degrade proteins in extracellular environment to promote metastasis. The proteases we are currently investigating are matrix metalloproteinases (MMPs) 2 and 9, hepsin, matrilysin, and TMPRSS2, all of which are increased in CRPC. Thus far, we've observed an increase in MMP2 and matrilysin. Based on our in vitro studies, we predict that PC3 cells expressing wildtype or mutant AR (ARΔNLS) may be more aggressive and metastatic than the parental line in vivo. To test this hypothesis, we have created stable clones that express a tetracycline-inducible shRNA targeting either AR or Src, to assess the metastatic and survival potential of these cells in an orthotopic xenograft model. Citation Format: Jelani C. Zarif, Laura E. Lamb, Cindy K. Miranti. Androgen receptor nongenomic regulation of invasion and metastasis of prostate tumor cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A5.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.PRCA2012-A5
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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