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The Pro-cancer Function of Soluble Guanylate Cyclase Alpha-1 in Prostate Cancer Progression

Hsieh, Chen-Lin
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1278952517

Abstract Details

2010, Doctor of Philosophy, University of Toledo, Biology (Cell-Molecular Biology).
A large body of evidence demonstrated that AR involves in the development of CRPC despite of the hormonal treatment. One common scenario is AR overexpression, which is observed in 22%~30% of castration-resistant prostate cancer (CRPC). Thus, we postulate that expression of a hyperactive AR would be sufficient to drive hormone-dependent prostate cancer cells to castration-resistant ones. To test this hypothesis, we generated LNCaP cell lines that stably overexpress a VP16-AR hybrid protein. Interestingly, VP16-AR cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth, suggesting that hyperactive AR is sufficient to transform prostate cancer cells to CRPC. Our lab has identified soluble guanylate cyclase alpha-1 (sGCα1) as a novel androgen-regulated gene involved in prostate cancer cell proliferation. The classical biological function of guanylyl cyclase (GC) is to catalyze cGMP synthesis in nitric oxide (NO) signaling. Our data demonstrated that the sGCα1 effect on prostate cancer cell growth is independent of the classical mediators of NO signaling, suggesting that sGCα1 acts via a novel signaling pathway. Interestingly, a gene expression profile from primary prostate tumors demonstrated that the expression of sGCα1 and p53 is highly correlated. Importantly, immunohistochemical results showed that p53 is colocalized with sGCα1 in the cytoplasm of localized prostate tumor specimens. Overexpression of sGCα1 led to p53 cytoplasmic accumulation, whereas knockdown of endogenous sGCα1 resulted in redistribution of p53 in the nucleus, suggesting that sGCα1 modulates p53 subcellular localization. Our data show that sGCα1 represses p53 transcriptional activity distinct from its guanylate cyclase function. PCR array analysis indicated that sGCα1 regulation of p53 affects the expression of certain p53-regulated genes involved in apoptosis. Interestingly, LNCaP cells that stably overexpress sGCα1 exhibited a marked induction of Akt kinase, a mediator of PI3K signaling that is very important in the proliferation of prostate cancer cells. Thus, we propose two mechanisms by which sGCα1 mediates prostate cancer progression: first, sGCα1 compromises p53 transcriptional activity by retaining p53 in the cytoplasm and blocking apoptosis; the second is that sGCα1 induces activation of Akt and its downstream targets, leading to enhanced cell proliferation. In view of the pro-cancer roles of sGCα1 in mediating prostate cancer progression, we attempted to disrupt sGCα1 activity using interacting peptides. Four peptides, designated as Peptide A, B, C, and D, were synthesized, based on four known sGCα1-interaction domains found on sGCβ1, its heterodimerization partner mediating NO signaling. Interestingly, only Peptide A had a rapid and strongly cytotoxic effect on both androgen-dependent and androgen-independent prostate cancer cells. Interestingly, Peptide A had little or no effect on cancer cells lacking sGCα1 expression, suggesting that this peptide acts via endogenous sGCα1. In support of this, immunocytochemistry analysis showed a cytoplasmic co-localization of Peptide A and sGCα1. Importantly, an LNCaP xenograft mouse model showed that the treatment with Peptide A-8R completely stopped the tumor growth. Therefore, Peptide A may be a novel therapeutic agent against prostate cancer.
Lirim Shemshedini, PhD (Committee Chair)
Scott Leisner, PhD (Committee Member)
Manohar Ratnam, PhD (Committee Member)
Edwin Sanchez, PhD (Committee Member)
William Taylor, PhD (Committee Member)
184 p.
Biology
GUCY1A3; Soluble Guanylate Cyclase Alpha-1; Prostate Cancer; PCa; Castration-Resistant Prostate Cancer; CRPC

Recommended Citations

Citations

  • Hsieh, C.-L. (2010). The Pro-cancer Function of Soluble Guanylate Cyclase Alpha-1 in Prostate Cancer Progression [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1278952517

    APA Style (7th edition)

  • Hsieh, Chen-Lin. The Pro-cancer Function of Soluble Guanylate Cyclase Alpha-1 in Prostate Cancer Progression. 2010. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1278952517.

    MLA Style (8th edition)

  • Hsieh, Chen-Lin. "The Pro-cancer Function of Soluble Guanylate Cyclase Alpha-1 in Prostate Cancer Progression." Doctoral dissertation, University of Toledo, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1278952517

    Chicago Manual of Style (17th edition)

toledo1278952517
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© 2010, all rights reserved.
This open access ETD is published by University of Toledo and OhioLINK.