Carey, Anne-Marie and Pramanik, Rashida and Nicholson, Linda J. and Dew, Tracy K. and Martin, Frank L. and Muir, Gordon H. and Morris, Jonathan D. H. (2007) Ras-MEK-ERK signaling cascade regulates androgen receptor element-inducible gene transcription and DNA synthesis in prostate cancer cells. International Journal of Cancer, 121 (3). pp. 520-527. ISSN 0020-7136Full text not available from this repository.
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.
|Journal or Publication Title:||International Journal of Cancer|
|Uncontrolled Keywords:||Ras • MEK • ERK • androgen • prostate cancer • refractory disease|
|Subjects:||G Geography. Anthropology. Recreation > GE Environmental Sciences|
|Departments:||Faculty of Science and Technology > Lancaster Environment Centre|
|Deposited By:||Mr Richard Ingham|
|Deposited On:||14 Jan 2010 10:25|
|Last Modified:||26 Jul 2012 16:56|
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