Faculty Collaboration Database

The Raf/MEK/extracellular signal-regulated kinase 1/2 pathway can mediate growth inhibitory and differentiation signaling via androgen receptor downregulation in prostate cancer cells. Exp Cell Res 2011 Nov 01;317(18):2671-82

Date

08/30/2011

Pubmed ID

21871886

Pubmed Central ID

PMC3189339

DOI

10.1016/j.yexcr.2011.08.008

Scopus ID

2-s2.0-80053574588 (requires institutional sign-in at Scopus site)   36 Citations

Abstract

Upregulated ERK1/2 activity is correlated with androgen receptor (AR) downregulation in certain prostate cancer (PCa) that exhibits androgen deprivation-induced neuroendocrine differentiation, but its functional relevance requires elucidation. We found that sustained ERK1/2 activation using active Raf or MEK1/2 mutants is sufficient to induce AR downregulation at mRNA and protein levels in LNCaP. Downregulation of AR protein, but not mRNA, was blocked by proteasome inhibitors, MG132 and bortezomib, indicating that the pathway regulation is mediated at multiple points. Ectopic expression of a constitutively active AR inhibited Raf/MEK/ERK-mediated regulation of the differentiation markers, neuron-specific enolase and neutral endopeptidase, and the cyclin-dependent kinase inhibitors, p16(INK4A) and p21(CIP1), but not Rb phosphorylation and E2F1 expression, indicating that AR has a specific role in the pathway-mediated differentiation and growth inhibitory signaling. However, despite the sufficient role of Raf/MEK/ERK, its inhibition using U0126 or ERK1/2 knockdown could not block androgen deprivation-induced AR downregulation in an LNCaP neuroendocrine differentiation model, suggesting that additional signaling pathways are involved in the regulation. We additionally report that sustained Raf/MEK/ERK activity can downregulate full length as well as hormone binding domain-deficient AR isoforms in androgen-refractory C4-2 and CWR22Rv1, but not in LAPC4 and MDA-PCa-2b. Our study demonstrates a novel role of the Raf/MEK/ERK pathway in regulating AR expression in certain PCa types and provides an insight into PCa responses to its aberrant activation.

Author List

Hong SK, Kim JH, Lin MF, Park JI

Author

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Differentiation
Cell Proliferation
Down-Regulation
Humans
MAP Kinase Kinase Kinases
Male
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Prostatic Neoplasms
Receptors, Androgen
Signal Transduction
Tumor Cells, Cultured
raf Kinases