title: Ras-MEK-ERK signaling cascade regulates androgen receptor element-inducible gene transcription and DNA synthesis in prostate cancer cells.
abstract: 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.
authors.affiliation: King's College London, Rayne Institute, London, United Kingdom.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Carey
authors.forename: Rashida
authors.initials: R
authors.lastname: Pramanik
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Nicholson
authors.forename: Tracy K
authors.initials: TK
authors.lastname: Dew
authors.forename: Francis L
authors.initials: FL
authors.lastname: Martin
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Muir
authors.forename: Jonathan D H
authors.initials: JD
authors.lastname: Morris
mesh_terms: D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D002070:Butadienes; D004273:DNA, Neoplasm; C404062:FTI 276; D009570:Nitriles; D011944:Receptors, Androgen; C113580:U 0126; D008715:Methionine; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins