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Pangburn HA, Kraus H, Ahnen DJ, et al. Sulindac metabolites inhibit epidermal growth factor receptor activation and expression. J Carcinog. 2005;4:16doi: 10.1186/1477-3163-4-16.
Pangburn, H. A., Kraus, H., Ahnen, D. J., & Rice, P. L. (2005). Sulindac metabolites inhibit epidermal growth factor receptor activation and expression. Journal of carcinogenesis, 416. https://doi.org/10.1186/1477-3163-4-16
Pangburn, Heather A, et al. "Sulindac metabolites inhibit epidermal growth factor receptor activation and expression." Journal of carcinogenesis vol. 4 (2005): 16. doi: https://doi.org/10.1186/1477-3163-4-16
Pangburn HA, Kraus H, Ahnen DJ, Rice PL. Sulindac metabolites inhibit epidermal growth factor receptor activation and expression. J Carcinog. 2005 Sep 02;4:16. doi: 10.1186/1477-3163-4-16. PMID: 16138927; PMCID: PMC1208922.
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J Carcinog. 2005 Sep 02;4:16. doi: 10.1186/1477-3163-4-16.

Sulindac metabolites inhibit epidermal growth factor receptor activation and expression.

Journal of carcinogenesis

Heather A Pangburn, Hanna Kraus, Dennis J Ahnen, Pamela L Rice

Affiliations

  1. Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, USA. [email protected]

PMID: 16138927 PMCID: PMC1208922 DOI: 10.1186/1477-3163-4-16

Abstract

BACKGROUND: 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 in vitro and inhibit growth of neoplastic colonic mucosa in vivo 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).

METHODS: 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 alpha-tubulin.

RESULTS: 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.

CONCLUSION: 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.

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