Abstract
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.
Highlights
Non–small-cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States, with low 5-year survival rates of 12% to 15% [1]
In our examination of NSCLC, we show that 15-hydroxyprostaglandin dehydrogenase (15-PGDH) protein and mRNA are down-regulated in multiple subtypes of NSCLC
To investigate whether 15-PGDH is down-regulated in NSCLC, we examined 15-PGDH protein levels in 39 lung cancer cell lines and 6 paired normal lung versus lung tumor tissues by Western blotting (Fig. 1A and B; Supplementary Table S1)
Summary
Non–small-cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States, with low 5-year survival rates of 12% to 15% [1]. Treatment with the EGF receptor (EGFR)– specific inhibitor erlotinib negated the effects of EGF and increased the protein levels of PGDH above control colon cancer cells. To investigate whether 15-PGDH is down-regulated in NSCLC, we examined 15-PGDH protein levels in 39 lung cancer cell lines and 6 paired normal lung versus lung tumor tissues by Western blotting (Fig. 1A and B; Supplementary Table S1).
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