Inhibition of epidermal growth factor receptor kinase induces protease- dependent apoptosis in human colon cancer cells

Jr Karnes, S. G. Weller, P. N. Adjei, T. J. Kottke, K. S. Glenn, G. J. Gores, S. H. Kaufmann

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Background and Aims: The epidermal growth factor receptor (EGFR) is under investigation as a therapeutic target for cancers. Colon cancer cell lines are variably dependent on autocrine stimulation of EGFR. We therefore examined the effects of a selective EGFR tyrosine kinase inhibitor, PD 153035, on proliferation and survival of five colon cancer cell lines whose autonomous proliferation is either EGFR ligand dependent or EGFR ligand independent. Methods: Effects of inhibitors were screened by MTS growth assays, [3H]thymidine incorporation, terminal deoxynucleotidyl transferase- mediated deoxyuridine triphosphate nick-end labeling assay, fluorescence microscopy, immunoblotting, and in vitro protease assays. Results: PD 153035 caused dose-dependent cytostasis (200 nmol/L to 1 μmol/L) and apoptosis (>10 μmol/L) in ligand-dependent cell lines and caused variable apoptosis (>10 μmol/L) but no cytostasis in ligand-independent cell lines. Apoptosis induced by 10 μmol/L PD 153035 was not associated with induction of p53 protein expression but was accompanied by activation of caspases that cleave poly(ADP-ribose) polymerase, lamin B1, and Bcl-2. Inhibition of caspase 3- like protease activity by DEVD-fluoromethylketone significantly delayed the onset of PD 153035-induced apoptosis. Conclusions: The EGFR tyrosine kinase inhibitor PD 153035 induces cytostasis and caspase-dependent apoptosis in EGFR ligand-dependent colon cancer cell lines. These observations encourage further investigation of EGFR tyrosine kinase inhibitors for treatment of colorectal neoplasms.

Original languageEnglish (US)
Pages (from-to)930-939
Number of pages10
JournalGastroenterology
Volume114
Issue number5
DOIs
StatePublished - Jan 1 1998

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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