AKT Regulates Androgen Receptor-dependent Growth and PSA Expression in Prostate Cancer

  • Margarita Mikhailova
  • Yu Wang
  • Roble Bedolla
  • Xiao-Hua Lu
  • Jeffrey I. Kreisberg
  • Paramita M. Ghosh
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)


Recurrent prostate cancer (PC) is usually treated with androgen deprivation therapy, which, despite initial success, eventually fails due to the development of androgen-independent PC. Androgen deprivation stimulates a significant increase in the phosphorylation (activation) of Akt, a serine/threonine kinase, which regulates cell growth and survival. Hence, we asked whether the increase in Akt phosphorylation contributes to the development of androgen independence. Akt regulates transcriptional activity of the androgen receptor (AR), and our data show that Akt-stimulated AR transcriptional activity is dependent on androgen-binding to the AR. PC proliferation has both androgen-sensitive and insensitive components. The androgen sensitive component is Akt-dependent, while the androgen-insensitive is not. However, Akt-induced cell survival is largely AR independent, suggesting that the cell stimulates Akt phosphorylation when subjected to androgen deprivation as an alternate pathway to maintain survival.


Prostate Cancer Androgen Receptor Androgen Deprivation Therapy LNCaP Cell Recurrent Prostate Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Edwards J, Bartlett JM (2005) The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 1: Modifications to the androgen receptor. BJU Int 95, 1320–1326.PubMedCrossRefGoogle Scholar
  2. 2.
    Petrylak D (2005) Therapeutic options in androgen-independent prostate cancer: building on docetaxel. BJU Int 96 (Suppl 2), 41–46.PubMedCrossRefGoogle Scholar
  3. 3.
    Murillo H, Huang H, Schmidt LJ, et al. (2001) Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. Endocrinology 142, 4795–4805.PubMedCrossRefGoogle Scholar
  4. 4.
    Ghosh PM, Malik SN, Bedolla RG, et al. (2005) Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation. Endocr Relat Cancer 12, 119–134.PubMedCrossRefGoogle Scholar
  5. 5.
    Majumder PK, Sellers WR (2005) Akt-regulated pathways in prostate cancer. Oncogene 24, 7465–7474.PubMedCrossRefGoogle Scholar
  6. 6.
    Graff JR, Konicek BW, McNulty AM, et al. (2000) Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem 275, 24500–24505.PubMedCrossRefGoogle Scholar
  7. 7.
    Culig Z, Hobisch A, Bartsch G, et al. (2000) Androgen receptor – an update of mechanisms of action in prostate cancer. Urol Res 28, 211–219.PubMedCrossRefGoogle Scholar
  8. 8.
    Lin HK, Yeh S, Kang HY, et al. (2001) Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci USA 98, 7200–7205.PubMedCrossRefGoogle Scholar
  9. 9.
    Wen Y, Hu MC, Makino K, et al. (2000) HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res 60, 6841–6845.PubMedGoogle Scholar
  10. 10.
    Xin L, Teitell MA, Lawson DA, et al. (2006) Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor. Proc Natl Acad Sci USA 103, 7789–7794.PubMedCrossRefGoogle Scholar
  11. 11.
    Feldman BJ, Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1, 34–45.PubMedCrossRefGoogle Scholar
  12. 12.
    Wu X, Senechal K, Neshat MS, et al. (1998) The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA 95, 15587–15591.PubMedCrossRefGoogle Scholar
  13. 13.
    Thalmann GN, Anezinis PE, Chang SM, et al. (1994) Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res 54, 2577–2581.PubMedGoogle Scholar
  14. 14.
    Haag P, Bektic J, Bartsch, et al. (2005) Androgen receptor down regulation by small interference RNA induces cell growth inhibition in androgen sensitive as well as in androgen independent prostate cancer cells. J Steroid Biochem Mol Biol 96, 251–258.PubMedCrossRefGoogle Scholar
  15. 15.
    Czauderna F, Fechtner M, Aygun H, et al. (2003) Functional studies of the PI(3)-kinase signalling pathway employing synthetic and expressed siRNA. Nucleic Acids Res 31, 670–682.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Margarita Mikhailova
  • Yu Wang
  • Roble Bedolla
  • Xiao-Hua Lu
  • Jeffrey I. Kreisberg
  • Paramita M. Ghosh
    • 1
  1. 1.Research ServicesVA Northern California HCSMatherUSA

Personalised recommendations