Inhibition of epidermal growth factor-stimulated EGF receptor tyrosine kinase activity in A431 human epidermoid carcinoma cells by polyamines

• Published in: Cell growth & differentiation Vol. 6; no. 2; pp. 115 - 121
• Main Authors: FAALAND, C. A, LASKIN, J. D, THOMAS, T. J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.1995
• Subjects: Biogenic Polyamines - metabolism; Biogenic Polyamines - pharmacology; Biological and medical sciences; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - metabolism; Cell physiology; Epidermal Growth Factor - antagonists & inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Molecular and cellular biology; Phosphorylation; Receptor Protein-Tyrosine Kinases - drug effects; Signal transduction; Tumor Cells, Cultured; Human; Signal transduction; Squamous cell carcinoma; Polyamine; Cell line; Epidermal growth factor; Enzyme; Transferases; Protein-tyrosine kinase; Biological receptor
• ISSN: 1044-9523; 2377-0732

Polyamines--putrescine, spermidine, and spermine--are ubiquitous cellular components that play an important role in cell growth and differentiation. Using A431 cells, a cell line that overexpresses the epidermal growth factor (EGF) receptor, we found that polyamines modulate EGF-mediated growth inhibition. The natural polyamine, putrescine, was the most effective, followed by diamines containing lower and higher methylene bridging between the amino groups. To understand the mechanism, we examined the effects of polyamines on EGF-mediated signal transduction in A431 cells. All three polyamines partially inhibited EGF-receptor tyrosine kinase activity in a dose-dependent manner. The maximal inhibition was 75% with spermidine. Polyamine effects were exerted 12-16 h after treatment, although HPLC analysis revealed uptake of polyamines within 1 h. Homologues of putrescine had no significant effect on tyrosine kinase activity, indicating structural specificity of naturally occurring polyamines in this process. Amine oxidase inhibitors did not alter spermidine and spermine-mediated effects, suggesting that the inhibition of tyrosine kinase activity was not a consequence of the oxidative metabolism of polyamines. Difluoromethylornithine, a specific inhibitor of polyamine biosynthesis, did not affect EGF receptor tyrosine kinase activity. Polyamines also had no effect on EGF receptor levels or EGF-EGF receptor high-affinity binding, indicating that they are not competitive inhibitors of the EGF receptor tyrosine kinase. Our results suggest that polyamine action in A431 cells involves modulation of EGF receptor signal transduction pathways.