The role of STAT -3 in androgen-dependent prostate cancer

Prostate cancer is the third-leading cause of male cancer-related deaths and the prostate gland is the leading site of new male cancer cases in Canada. Prostate tumour growth and survival is initially androgen-dependent and primary treatments include radiation and surgery. Androgen withdrawal the...

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Main Author: Gardiner, Clare Elizabeth
Format: Others
Language:English
Published: 2009
Online Access:http://hdl.handle.net/2429/15205
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spelling ndltd-UBC-oai-circle.library.ubc.ca-2429-152052018-01-05T17:37:43Z The role of STAT -3 in androgen-dependent prostate cancer Gardiner, Clare Elizabeth Prostate cancer is the third-leading cause of male cancer-related deaths and the prostate gland is the leading site of new male cancer cases in Canada. Prostate tumour growth and survival is initially androgen-dependent and primary treatments include radiation and surgery. Androgen withdrawal therapy is used as a secondary treatment, to decrease the circulating supply of androgens in the body. While primary and secondary treatment can reduce tumour growth, in many cases the epithelial cells can begin to proliferate again and the tumour will acquire an androgen-independent phenotype. The objective of this thesis is to clarify the biochemical interactions that occur in IL-6 and AR pathway cross-talk. Since EGF also activates STAT-3, we included analysis of EGF cross-talk with the IL-6 and AR pathways. We investigated the potential for pathway interaction in LNCaP cells by using AR and STAT luciferase reporter constructs in the presence of IL-6, R-1881 and EGF stimulation. To verify the necessity of STAT-3 to the observed pathway interactions, we used shRNA to downregulate STAT-3 expression. In addition, we studied the role of STAT-3 in LNCaP xenograft tumour growth and serum PSA production in male nude mice. Our findings confirm that androgen can augment STAT-mediated gene transcription and growth factors such as IL-6 and EGF can augment AR-mediated gene transcription. Based on the ability of STAT-3 antisense ODN treatment to suppress serum PSA levels and tumour growth in vivo, and our in vitro findings that indicate an inability of STAT-3 shRNA to suppress EGF and IL-6-mediated augmentation of androgen-stimulated AR-mediated gene transcription, we propose that STAT-3 activation may not be directly involved in AR transactivation. Other growth factor pathways that occur in parallel to STAT-3 activation are likely responsible for AR transactivation via AR co-regulators. We conclude that STAT-3 has a role in regulating prostate cancer growth and survival, under androgen-deprived conditions, that indirectly affects AR activity. Medicine, Faculty of Medicine, Department of Experimental Medicine, Division of Graduate 2009-11-17T22:42:47Z 2009-11-17T22:42:47Z 2003 2003-11 Text Thesis/Dissertation http://hdl.handle.net/2429/15205 eng For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. 13913261 bytes application/pdf
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description Prostate cancer is the third-leading cause of male cancer-related deaths and the prostate gland is the leading site of new male cancer cases in Canada. Prostate tumour growth and survival is initially androgen-dependent and primary treatments include radiation and surgery. Androgen withdrawal therapy is used as a secondary treatment, to decrease the circulating supply of androgens in the body. While primary and secondary treatment can reduce tumour growth, in many cases the epithelial cells can begin to proliferate again and the tumour will acquire an androgen-independent phenotype. The objective of this thesis is to clarify the biochemical interactions that occur in IL-6 and AR pathway cross-talk. Since EGF also activates STAT-3, we included analysis of EGF cross-talk with the IL-6 and AR pathways. We investigated the potential for pathway interaction in LNCaP cells by using AR and STAT luciferase reporter constructs in the presence of IL-6, R-1881 and EGF stimulation. To verify the necessity of STAT-3 to the observed pathway interactions, we used shRNA to downregulate STAT-3 expression. In addition, we studied the role of STAT-3 in LNCaP xenograft tumour growth and serum PSA production in male nude mice. Our findings confirm that androgen can augment STAT-mediated gene transcription and growth factors such as IL-6 and EGF can augment AR-mediated gene transcription. Based on the ability of STAT-3 antisense ODN treatment to suppress serum PSA levels and tumour growth in vivo, and our in vitro findings that indicate an inability of STAT-3 shRNA to suppress EGF and IL-6-mediated augmentation of androgen-stimulated AR-mediated gene transcription, we propose that STAT-3 activation may not be directly involved in AR transactivation. Other growth factor pathways that occur in parallel to STAT-3 activation are likely responsible for AR transactivation via AR co-regulators. We conclude that STAT-3 has a role in regulating prostate cancer growth and survival, under androgen-deprived conditions, that indirectly affects AR activity. === Medicine, Faculty of === Medicine, Department of === Experimental Medicine, Division of === Graduate
author Gardiner, Clare Elizabeth
spellingShingle Gardiner, Clare Elizabeth
The role of STAT -3 in androgen-dependent prostate cancer
author_facet Gardiner, Clare Elizabeth
author_sort Gardiner, Clare Elizabeth
title The role of STAT -3 in androgen-dependent prostate cancer
title_short The role of STAT -3 in androgen-dependent prostate cancer
title_full The role of STAT -3 in androgen-dependent prostate cancer
title_fullStr The role of STAT -3 in androgen-dependent prostate cancer
title_full_unstemmed The role of STAT -3 in androgen-dependent prostate cancer
title_sort role of stat -3 in androgen-dependent prostate cancer
publishDate 2009
url http://hdl.handle.net/2429/15205
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