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Inhibition of epidermal growth factor receptor signaling elevates 15-hydroxyprostaglandin dehydrogenase in non-small-cell lung cancer.

Yang L, Amann JM, Kikuchi T, Porta R, Guix M, Gonzalez A, Park KH, Billheimer D, Arteaga CL, Tai HH, DuBois R, Carbone DP, Johnson DH
Cancer Res. 2007 67 (12): 5587-93

PMID: 17575121 · DOI:10.1158/0008-5472.CAN-06-2287

Evidence indicates that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of non-small-cell lung cancer (NSCLC). In addition to overproduction by COX-2, PGE2 concentrations also depend upon the levels of the PGE2 catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH). We find a dramatic down-regulation of PGDH protein in NSCLC cell lines and in resected human tumors when compared with matched normal lung. Affymetrix array analysis of 10 normal lung tissue samples and 49 resected lung tumors revealed a much lower expression of PGDH transcripts in all NSCLC histologic groups. In addition, treatment with the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) erlotinib increased the expression of 15-PGDH in a subset of NSCLC cell lines. This effect may be due in part to an inhibition of the extracellular signal-regulated kinase (ERK) pathway as treatment with mitogen-activated protein kinase kinase (MEK) inhibitor U0126 mimics the erlotinib results. We show by quantitative reverse transcription-PCR that the transcript levels of ZEB1 and Slug transcriptional repressors are dramatically reduced in a responsive cell line upon EGFR and MEK/ERK inhibition. In addition, the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription. As these repressors function by recruiting histone deacetylases to promoters, it is likely that PGDH is repressed by an epigenetic mechanism involving histone deacetylation, resulting in increased PGE2 activity in tumors. This effect is reversible in a subset of NSCLC upon treatment with an EGFR TKI.

MeSH Terms (21)

Animals Blotting, Western Carcinoma, Non-Small-Cell Lung Cell Line, Tumor Electrophoretic Mobility Shift Assay Epigenesis, Genetic ErbB Receptors Extracellular Signal-Regulated MAP Kinases Gene Expression Homeodomain Proteins Humans Hydroxyprostaglandin Dehydrogenases Lung Neoplasms Oligonucleotide Array Sequence Analysis Protein Kinase Inhibitors Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Snail Family Transcription Factors Transcription, Genetic Transcription Factors Zinc Finger E-box-Binding Homeobox 1

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