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Br J Surg. 2007 Jan;94(1):106-12.

Mechanisms of endothelin 1-stimulated proliferation in colorectal cancer cell lines.

Author information

1
Department of Surgery, Royal Free and University College Medical School, University College London, London, UK.

Abstract

BACKGROUND:

The peptide endothelin (ET) 1 promotes proliferation in a number of epithelial cancers. The aim of this study was to identify the mechanism of ET-1-stimulated proliferation in colorectal cancer cells in vitro.

METHODS:

The effects of ET-1 on colorectal cancer cell lines HT29, LIM1215 and SW620 were studied. Cells were cultured with ET-1 plus antagonists/inhibitors to ET(A) or ET(B) receptors, G protein subtypes, phosphoinositide 3-kinase (PI3K) or protein kinase C (PKC). DNA replication and apoptosis were investigated by 5-bromo-2'-deoxyuridine incorporation and Annexin V staining. Transactivation of the epidermal growth factor (EGF) receptor was investigated by blockade of the receptor in the presence of ET-1, measurement of levels of phosphorylated EGF receptor in the presence of ET-1, and comparing the effects of ET-1 and EGF on cell proliferation.

RESULTS:

ET-1 significantly stimulated growth of all cell lines via ET(A) receptors. ET-1 stimulated DNA replication, not apoptosis. ET-1-stimulated growth was inhibited by antagonism of pertussis toxin-sensitive G proteins, PI3K and PKC. Inhibition of the EGF receptor reduced the effect of ET-1. ET-1 increased levels of phosphorylated EGF receptor via the ET(A) receptor.

CONCLUSION:

ET-1 increased DNA replication in colorectal cancer cells via the ET(A) receptor. This mitogenic action was mediated via pertussis toxin-sensitive G proteins, PI3K, PKC and transactivation of the EGF receptor.

PMID:
17078114
DOI:
10.1002/bjs.5536
[Indexed for MEDLINE]

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