fti-276 and Prostatic-Neoplasms

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.

Topics: Butadienes; Cell Proliferation; DNA, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Male; Methionine; Mitogen-Activated Protein Kinase Kinases; Neoplasms, Hormone-Dependent; Nitriles; Prostatic Neoplasms; ras Proteins; Receptors, Androgen; Signal Transduction; Transcription, Genetic; Tumor Cells, Cultured