Sulindac metabolites inhibit epidermal growth factor receptor activation and expression

<p>Abstract</p> <p>Background</p> <p>Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased mortality from colorectal cancer (CRC). NSAIDs induce apoptotic cell death in colon cancer cells <it>in vitro </it>and inhibit gr...

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Main Authors: Pangburn Heather A, Kraus Hanna, Ahnen Dennis J, Rice Pamela L
Format: Article
Language:English
Published: Wolters Kluwer Medknow Publications 2005-09-01
Series:Journal of Carcinogenesis
Online Access:http://www.carcinogenesis.com/content/4/1/16
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spelling doaj-f7305bb3c02c4fc4a7695ff2676091ea2020-11-24T23:28:14ZengWolters Kluwer Medknow PublicationsJournal of Carcinogenesis0974-67731477-31632005-09-01411610.1186/1477-3163-4-16Sulindac metabolites inhibit epidermal growth factor receptor activation and expressionPangburn Heather AKraus HannaAhnen Dennis JRice Pamela L<p>Abstract</p> <p>Background</p> <p>Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased mortality from colorectal cancer (CRC). NSAIDs induce apoptotic cell death in colon cancer cells <it>in vitro </it>and inhibit growth of neoplastic colonic mucosa <it>in vivo </it>however, the biochemical mechanisms required for these growth inhibitory effects are not well defined. We previously reported that metabolites of the NSAID sulindac downregulate extracellular-signal regulated kinase 1/2 (ERK1/2) signaling and that this effect is both necessary and sufficient for the apoptotic effects of these drugs. The goal of this project was to specifically test the hypothesis that sulindac metabolites block activation and/or expression of the epidermal growth factor (EGF) receptor (EGFR).</p> <p>Methods</p> <p>HT29 human colon cancer cells were treated with EGF, alone, or in the presence of sulindac sulfide or sulindac sulfone. Cells lysates were assayed by immunoblotting for phosphorylated EGFR (pEGFR, pY1068), total EGFR, phosphorylated ERK1/2 (pERK1/2), total ERK1/2, activated caspase-3, and α-tubulin.</p> <p>Results</p> <p>EGF treatment rapidly induced phosphorylation of both EGFR and ERK1/2 in HT29 colon cancer cells. Pretreatment with sulindac metabolites for 24 h blocked EGF-induced phosphorylation of both EGFR and ERK1/2 and decreased total EGFR protein expression. Under basal conditions, downregulation of pEGFR and total EGFR was detected as early as 12 h following sulindac sulfide treatment and persisted through at least 48 h. Sulindac sulfone induced downregulation of pEGFR and total EGFR was detected as early as 1 h and 24 h, respectively, following drug treatment, and persisted through at least 72 h. EGFR downregulation by sulindac metabolites was observed in three different CRC cell lines, occurred prior to the observed downregulation of pERK1/2 and induction of apoptosis by these drugs, and was not dependent of caspase activation.</p> <p>Conclusion</p> <p>These results suggest that downregulation of EGFR signaling by sulindac metabolites may occur, at least in part, by inhibiting activation and expression of EGFR. Inhibition of EGFR signaling may account for part of the growth inhibitory and chemopreventive effects of these compounds.</p> http://www.carcinogenesis.com/content/4/1/16
collection DOAJ
language English
format Article
sources DOAJ
author Pangburn Heather A
Kraus Hanna
Ahnen Dennis J
Rice Pamela L
spellingShingle Pangburn Heather A
Kraus Hanna
Ahnen Dennis J
Rice Pamela L
Sulindac metabolites inhibit epidermal growth factor receptor activation and expression
Journal of Carcinogenesis
author_facet Pangburn Heather A
Kraus Hanna
Ahnen Dennis J
Rice Pamela L
author_sort Pangburn Heather A
title Sulindac metabolites inhibit epidermal growth factor receptor activation and expression
title_short Sulindac metabolites inhibit epidermal growth factor receptor activation and expression
title_full Sulindac metabolites inhibit epidermal growth factor receptor activation and expression
title_fullStr Sulindac metabolites inhibit epidermal growth factor receptor activation and expression
title_full_unstemmed Sulindac metabolites inhibit epidermal growth factor receptor activation and expression
title_sort sulindac metabolites inhibit epidermal growth factor receptor activation and expression
publisher Wolters Kluwer Medknow Publications
series Journal of Carcinogenesis
issn 0974-6773
1477-3163
publishDate 2005-09-01
description <p>Abstract</p> <p>Background</p> <p>Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased mortality from colorectal cancer (CRC). NSAIDs induce apoptotic cell death in colon cancer cells <it>in vitro </it>and inhibit growth of neoplastic colonic mucosa <it>in vivo </it>however, the biochemical mechanisms required for these growth inhibitory effects are not well defined. We previously reported that metabolites of the NSAID sulindac downregulate extracellular-signal regulated kinase 1/2 (ERK1/2) signaling and that this effect is both necessary and sufficient for the apoptotic effects of these drugs. The goal of this project was to specifically test the hypothesis that sulindac metabolites block activation and/or expression of the epidermal growth factor (EGF) receptor (EGFR).</p> <p>Methods</p> <p>HT29 human colon cancer cells were treated with EGF, alone, or in the presence of sulindac sulfide or sulindac sulfone. Cells lysates were assayed by immunoblotting for phosphorylated EGFR (pEGFR, pY1068), total EGFR, phosphorylated ERK1/2 (pERK1/2), total ERK1/2, activated caspase-3, and α-tubulin.</p> <p>Results</p> <p>EGF treatment rapidly induced phosphorylation of both EGFR and ERK1/2 in HT29 colon cancer cells. Pretreatment with sulindac metabolites for 24 h blocked EGF-induced phosphorylation of both EGFR and ERK1/2 and decreased total EGFR protein expression. Under basal conditions, downregulation of pEGFR and total EGFR was detected as early as 12 h following sulindac sulfide treatment and persisted through at least 48 h. Sulindac sulfone induced downregulation of pEGFR and total EGFR was detected as early as 1 h and 24 h, respectively, following drug treatment, and persisted through at least 72 h. EGFR downregulation by sulindac metabolites was observed in three different CRC cell lines, occurred prior to the observed downregulation of pERK1/2 and induction of apoptosis by these drugs, and was not dependent of caspase activation.</p> <p>Conclusion</p> <p>These results suggest that downregulation of EGFR signaling by sulindac metabolites may occur, at least in part, by inhibiting activation and expression of EGFR. Inhibition of EGFR signaling may account for part of the growth inhibitory and chemopreventive effects of these compounds.</p>
url http://www.carcinogenesis.com/content/4/1/16
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