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Ras-MEK-ERK signaling cascade regulates androgen receptor element-inducible gene transcription and DNA synthesis in prostate cancer cells.

Research output: Contribution to journalJournal article

  • Anne-Marie Carey
  • Rashida Pramanik
  • Linda J. Nicholson
  • Tracy K. Dew
  • Frank L. Martin
  • Gordon H. Muir
  • Jonathan D. H. Morris
<mark>Journal publication date</mark>1/08/2007
<mark>Journal</mark>International Journal of Cancer
Issue number3
Number of pages8
Pages (from-to)520-527
<mark>Original language</mark>English


Treatment of prostate cancer (CaP) patients frequently involves androgen ablation, but resistance often develops and androgen-insensitive tumors emerge. The molecular basis for the development of refractory CaP that grows in an androgen-independent manner is poorly understood, but alterations in growth factor signaling pathways are likely to be involved. We examined the growth factor modulation of androgen-receptor element (ARE)-inducible luciferase reporter gene activity and consequent DNA synthesis as a measure of proliferative growth in androgen-dependent LNCaP or androgen-independent PC3 or DU145 CaP cells. The synthetic androgen R1881 stimulated ARE-inducible reporter gene activity and prostate-specific antigen expression in LNCaP cells and the MEK/ERK inhibitor U0126 or the anti-androgen bicalutamide (casodex) prevented both of these responses. Activated V12-Ha-Ras expression in LNCaP cells also stimulated ARE-inducible gene transcription, and U0126 or the farnesyltransferase inhibitor FTI-277 but not bicalutamide blocked this. ARE-inducible reporter gene activity was elevated already in PC3 cells, and ERK was constitutively activated in serum-starved LNCaP or DU145 cells. U0126 inhibited each of these responses and also inhibited DNA synthesis in all 3 CaP cell lines. These results demonstrate that chronic stimulation of the Ras-MEK-ERK signaling pathway can sustain ARE-inducible gene transcription and growth of CaP cells, and suggests that components of this pathway may offer targets for cancer therapy.