Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Androgen regulation of soluble guanylyl cyclaseα1 mediates prostate cancer cell proliferation

Oncogene volume 26, pages 1606–1615 (2007)Cite this article

Abstract

The growth and progression of prostate cancer are dependent on androgens and androgen receptor (AR), which act by modulating gene expression. Utilizing a gene microarray approach, we have identified the α1-subunit gene of soluble guanylyl cyclase (sGC) as a novel androgen-regulated gene. A heterodimeric cytoplasmic protein composed of one α and one β subunit, sGC mediates the widespread cellular effects of nitric oxide (NO). We report here that, in prostate cancer cells, androgens stimulate the expression of sGCα1. A cloned human sGCα1 promoter is activated by androgen in an AR-dependent manner, suggesting that sGCα1 may be a direct AR target gene. Disruption of sGCα1 expression severely compromises the growth of both androgen-dependent and androgen-independent AR-positive prostate cancer cells. Overexpression of sGCα1 alone is sufficient for stimulating prostate cancer cell proliferation. Interestingly, the major growth effect of sGCα1 is independent of NO and cyclic guanosine monophosphate, a major mediator of the sGC enzyme. These data strongly suggest that sGCα1 acts in prostate cancer via a novel pathway that does not depend on sGCβ1. Tissue studies show that sGCα1 expression is significantly elevated in advanced prostate cancer. Thus, sGCα1 may be an important mediator of the procarcinogenic effects of androgens.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 2
Figure 1
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Arnold JT, Isaacs JT . (2002). Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault. Endocr-Relat Cancer 9: 61–73.

    Article  CAS  Google Scholar 

  • Chang C, Kokontis J, Liao S . (1988). Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 240: 324–326.

    Article  CAS  Google Scholar 

  • Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R et al. (2004). Molecular determinants of resistance to antiandrogen therapy. Nat Med 10: 33–39.

    Article  Google Scholar 

  • Chen ME, Lin SH, Chung LW, Sikes RA . (1998). Isolation and characterization of Page-1 and Gage-7 new genes expressed in the LNCaP prostate cancer progression model that share homology with melanoma-associated antigens. J Biol Chem 273: 17618–17625.

    Article  CAS  Google Scholar 

  • Chen S-Y, Cai C, Fisher CJ, Zheng Z, Omwancha J, Hsieh C-L et al. (2006). c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation. Oncogene (in press) [Epub May 29].

  • Chen Z-J, Vetter M, Che D, Liu S, Tsai M-L, Chang C-H . (2002). The bradykinin/soluble guanylate cyclase signaling pathway is impaired in androgen-independent prostate cancer cells. Cancer Lett 177: 181–187.

    Article  CAS  Google Scholar 

  • Cunha GR, Donjacour AA, Cooke PS, Mee S, Bigsby RM, Higgins SJ et al. (1987). The endocrinology and developmental biology of the prostate. Endocr Rev 8: 338–362.

    Article  CAS  Google Scholar 

  • Eder IE, Hoffmann J, Rogatsch H, Schafer G, Zopf D, Bartsch G et al. (2002). Inhibition of LNCaP prostate tumor growth in vivo by an antisense oligonucleotide directed against the human androgen receptor. Cancer Gene Ther 9: 117–125.

    Article  CAS  Google Scholar 

  • Garcia-Arenas R, Lin FF, Lin D, Jin LP, Shih CC, Chang C et al. (1995). The expression of prostatic acid phosphatase is transcriptionally regulated in human prostate carcinoma cells. Mol Cell Endocrinol 111: 29–37.

    Article  CAS  Google Scholar 

  • Han G, Buchanan G, Ittmann M, Harris JM, Yu X, DeMayo FJ et al. (2005). Mutation of the androgen receptor causes oncogenic transformation of the prostate. Proc Natl Acad Sci USA 102: 1151–1156.

    Article  CAS  Google Scholar 

  • Heisler LE, Evangelou A, Lew AM, Trachtenberg J, Elsholtz HP, Brown TJ . (1997). Androgen-dependent cell cycle arrest and apoptotic death in PC-3 prostatic cell cultures expressing a full-length human androgen receptor. Mol Cell Endocrin 126: 59–73.

    Article  CAS  Google Scholar 

  • Horoszewicz JS, Leong SS, Kawinski E, Karr JP, Rosenthal H, Chu TM et al. (1983). LNCaP model of human prostatic carcinoma. Cancer Res 43: 1809–1818.

    CAS  PubMed  Google Scholar 

  • Igawa T, Lin FF, Lee MS, Karan D, Batra SK, Lin MF . (2002). Establishment and characterization of androgen-independent human prostate cancer LNCaP cell model. Prostate 50: 222–235.

    Article  CAS  Google Scholar 

  • Isaacs JT . (1984). Antagonistic effect of androgen on prostatic cell death. Prostate 5: 545–557.

    Article  CAS  Google Scholar 

  • Isaacs JT . (1994). Role of androgens in prostatic cancer. Vitam Horm 49: 433–502.

    Article  CAS  Google Scholar 

  • Isaacs JT . (1999). The biology of hormone refractory prostate cancer. Why does it develop? Urol Clin N Am 26: 263–273.

    Article  CAS  Google Scholar 

  • Jenster G . (1999). The role of the androgen receptor in the development and progression of prostate cancer. Semin Oncol 26: 407–421.

    CAS  PubMed  Google Scholar 

  • Jia L, Kim J, Shen H, Clark PE, Tilley WD, Coetzee GA . (2003). Androgen receptor activity at the prostate specific antigen locus: steroidal and nonsteroidal mechanisms. Mol Cancer Res 1: 385–392.

    CAS  PubMed  Google Scholar 

  • Jiang J, Wang LF, Fang YH, Jin FS, Jin WS . (2004). Proliferative response of human prostate cancer cell to hormone inhibited by androgen receptor antisense RNA. Chin Med J (Engl) 117: 684–688.

    CAS  Google Scholar 

  • Kastner P, Mark M, Chambon P . (1995). Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83: 859–869.

    Article  CAS  Google Scholar 

  • Koksal IT, Ozcan F, Kilicaslan I, Tefekli A . (2002). Expression of E-cadherin in prostate cancer in formalin-fixed, paraffin-embedded tissues: correlation with pathological features. Pathology 34: 223–238.

    Article  Google Scholar 

  • Krumenacker JS, Hanafy KA, Murad F . (2004). Regulation of nitric oxide and soluble guanylyl cyclase. Brain Res Bull 62: 505–515.

    Article  CAS  Google Scholar 

  • Krumenacker JS, Hyder SM, Murad F . (2001). Estradiol rapidly inhibits soluble guanylyl cyclase expression in rat uterus. Proc Natl Acad Sci USA 23: 170–178.

    Google Scholar 

  • Lee C, Sutkowski DM, Sensibar JA, Zelner D, Kim I, Amsel I et al. (1995). Regulation of proliferation and production of prostate-specific antigen in androgen-sensitive prostatic cancer cells, LNCaP, by dihydrotestosterone. Endocrine 136: 796–803.

    Article  CAS  Google Scholar 

  • Lin MF, Meng TC, Rao PS, Chang C, Schonthal AH, Lin FF . (1998). Expression of human prostatic acid phosphatase correlates with androgen-stimulated cell proliferation in prostate cancer cell lines. J Biol Chem 273: 5939–5947.

    Article  CAS  Google Scholar 

  • Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K et al. (1995). The nuclear receptor superfamily: the second decade. Cell 83: 835–839.

    Article  CAS  Google Scholar 

  • Meehan KL, Sadar MD . (2003). Androgens and androgen receptor in prostate and ovarian malignancies. Front Biosci 8: 780–800.

    Article  Google Scholar 

  • Mimeault M, Jouy N, Depreux P, Henichart JP . (2005). Synergistic antiproliferative and apoptotic effects induced by mixed epidermal growth factor receptor inhibitor ZD1839 and nitric oxide donor in human prostatic cancer cell lines. Prostate 62: 187–199.

    Article  CAS  Google Scholar 

  • Papandreou CN, Usmani B, Geng Y, Bogenrieder T, Freeman R, Wilk S et al. (1998). Neutral endopeptidase 24.11 loss in metastatic human prostate cancer contributes to androgen-independent progression. Nat Med 4: 50–57.

    Article  CAS  Google Scholar 

  • Postovit LM, Adams MA, Lash GE, Heaton JP, Graham CH . (2002). Oxygen-mediated regulation of tumor cell invasiveness. Involvement of a nitric oxide signaling pathway. J Biol Chem 277: 35370–35377.

    Article  Google Scholar 

  • Schrammel A, Behrends S, Schmidt K, Koesling D, Mayer B . (1996). Characterization of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one as a heme-site inhibitor of nitric oxide-sensitive guanylyl cyclase. Mol Pharmacol 50: 1–5.

    CAS  PubMed  Google Scholar 

  • Shenk JL, Fisher CJ, Chen SY, Zhou XF, Tillman K, Shemshedini L . (2001). p53 represses androgen-induced transactivation of prostate-specific antigen by disrupting hAR amino- to carboxyl-terminal interaction. J Biol Chem 276: 38472–38479.

    Article  CAS  Google Scholar 

  • Sinnaeve P, Chiche JD, Nong Z, Varenne O, Van Pelt N, Gillijns H et al. (2001). Soluble guanylate cyclase alpha(1) and beta(1) gene transfer increases NO responsiveness and reduces neointima formation after balloon injury in rats via antiproliferative and antimigratory effects. Circ Res 88: 103–109.

    Article  CAS  Google Scholar 

  • Trapman J, Cleutjens KB . (1997). Androgen-regulated gene expression in prostate cancer. Semin Cancer Biol 8: 29–36.

    Article  CAS  Google Scholar 

  • Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG et al. (2002). The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419: 624–629.

    Article  CAS  Google Scholar 

  • Young CYF, Murtha PE, Zhang J . (1994). Tumor-promoting phorbol ester-induced cell death and gene expression in a human prostate adenocarcinoma cell line. Oncol Res 6: 203–210.

    CAS  PubMed  Google Scholar 

  • Yuan S, Trachtenberg J, Mills GB, Brown TJ, Xu F, Keating A . (1993). Androgen-induced inhibition of cell proliferation in an androgen-insensitive prostate cancer cell line (PC-3) transfected with a human androgen receptor complementary DNA. Cancer Res 53: 1304–1311.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs P Chambon, H Gronemeyer and S Leisner for critical reading of this paper, Dr X Yuan for providing the AR siRNA oligonucleotides, and Dr D Moorhead and Mei Yang for help with statistical analysis of data. This work was supported by grants from National Institutes of Health and Ohio Cancer Research Associates.

Author information

Author notes

  1. S-Y Chen

    Present address: Harvard Medical School, 330 Brookline Avenue, Boston, MA, USA

  2. Z Zheng

    Present address: Medical University of Ohio, 3000 Arlington Avenue, Toledo, OH, USA

  3. J Omwancha

    Present address: Johns Hopkins University, 615 North Wolfe St., Baltimore, MD, USA

Authors and Affiliations

  1. Department of Biological Sciences, University of Toledo, Toledo, OH, USA

    C Cai, S-Y Chen, Z Zheng, J Omwancha & L Shemshedini

  2. Department of Medicine, Cancer Biology Program/Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    S-Y Chen & S P Balk

  3. Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    M-F Lin

Authors
  1. C Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S-Y Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Omwancha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M-F Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S P Balk
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Shemshedini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Shemshedini.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cai, C., Chen, SY., Zheng, Z. et al. Androgen regulation of soluble guanylyl cyclaseα1 mediates prostate cancer cell proliferation. Oncogene 26, 1606–1615 (2007). https://doi.org/10.1038/sj.onc.1209956

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209956

Keywords

This article is cited by

Search

Advanced search

Quick links