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

Treatment of prostate cancer (CaP) patients frequently involves androgen ablation, but resistance often develops and androgeninsensitive 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 antiandrogen 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 (if 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. (c) 2007 Wiley-Liss, Inc.