D'Antonio, Jason M.
(2007)
ANALYSIS OF ENDOTHELIN DURING ANDROGEN DEPRIVATION: IMPLICATIONS FOR PROSTATE CANCER PROGRESSION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Background. Androgen deprivation has been in use for the treatment of advanced prostate cancer since 1941; however, most patients develop resistance to treatment leading to incurable, androgen-independent disease. Previous reports have correlated endothelin A receptor (ETA) expression with increasing prostate cancer grade and stage, and have shown that endothelin-1 (ET-1) treatment of ETA-expressing prostate cancer cells inhibits apoptosis. ETA blockade has emerged as a potential strategy in the treatment of advanced prostate cancer. Here, the potential role of endothelin signaling in promoting prostate cancer cell survival during androgen ablation therapy is evaluated in efforts to establish the potential value of ETA blockade in improving hormone therapy.Methodology and Principle Findings. Androgen-dependent human prostate cancer cells were androgen deprived and evaluated for expression changes in ET-1, ETA, ETB, and AR. Ligand binding, real time quantitative PCR, and immunohistochemical studies show that androgen deprivation increased ET-1, ETA, ETB, and AR expression in prostate cancer cell lines, and ETA expression in human prostate tissue. Using the specific AR inhibitor bicalutamide, acute androgen receptor blockade increased prostate cancer cell ET-1 secretion. Following androgen deprivation, LNCaP cells acquired androgen independence (LNCaP-AI), but retained sensitivity to androgens. ET-1 treatment of ETA over-expressing prostate cancer cells induced a more rapid and sustained activation of Akt, and ETA blockade significantly reduced Akt activation. In vivo ETA blockade, in combination with castration, significantly reduced LNCaP xenograft cell growth, compared to either treatment alone. Affymetrix GeneChip HG-U133 Plus 2 expression array analysis of androgen deprived prostate cancer cells discovered dramatic changes in gene expression patterns throughout the transition to androgen independence. Lastly, the role of ETB signaling in prostate cancer cell apoptosis was examined but remains to be further elucidated.Conclusions and Significance. During androgen deprivation, prostate cancer cells up-regulate ET-1 and ETA expression. Upon engagement of ET-1, ETA invokes activation of the survival factor Akt. In vivo, ETA blockade plus castration inhibits prostate cancer growth. Collectively, these results implicate endothelin survival signaling in promoting progression to androgen-independent disease, and lend support to the targeted disruption of endothelin survival signaling in treating advanced, metastatic prostate cancer.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| D'Antonio, Jason M. | jad43@pitt.edu | JAD43 | |
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| ETD Committee: |
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| Date: |
29 August 2007 |
| Date Type: |
Completion |
| Defense Date: |
21 August 2007 |
| Approval Date: |
29 August 2007 |
| Submission Date: |
29 August 2007 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
androgen deprivation; endothelin; prostate cancer |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-08292007-110716/, etd-08292007-110716 |
| Date Deposited: |
10 Nov 2011 20:01 |
| Last Modified: |
14 Nov 2024 17:06 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9291 |
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