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

TY - JOUR

T1 - Ras-MEK-ERK signaling cascade regulates androgen receptor element-inducible gene transcription and DNA synthesis in prostate cancer cells

AU - Carey, Anne-Marie

AU - Pramanik, Rashida

AU - Nicholson, Linda J

AU - Muir, Gordon H

AU - Morris, Jonathan D H

N1 - Copyright (c) 2007 Wiley-Liss, Inc.

PY - 2007/8/1

Y1 - 2007/8/1

N2 - 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.

AB - 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.

KW - Butadienes

KW - Cell Proliferation

KW - DNA, Neoplasm

KW - Extracellular Signal-Regulated MAP Kinases

KW - Gene Expression Regulation, Neoplastic

KW - Genes, Reporter

KW - Humans

KW - Male

KW - Methionine

KW - Mitogen-Activated Protein Kinase Kinases

KW - Neoplasms, Hormone-Dependent

KW - Nitriles

KW - Prostatic Neoplasms

KW - Receptors, Androgen

KW - Signal Transduction

KW - Transcription, Genetic

KW - Tumor Cells, Cultured

KW - ras Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1002/ijc.22715

DO - 10.1002/ijc.22715

M3 - Article

C2 - 17415712

SN - 1097-0215

VL - 121

SP - 520

EP - 527

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 3

ER -