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Inverse regulation of human ERBB2 and epidermal growth factor receptors by tumor necrosis factor alpha
H Kalthoff1, C Roeder, J Gieseking
1Christian-Albrechts-Universität, Klinik für Allgemeine Chirurgie, Kiel, Federal Republic of Germany.
Abstract:
Recombinant human tumor necrosis factor (TNF) alpha decreased the expression of ERBB2 mRNA by stimulating p55 TNF receptors of pancreatic tumor cells. This decrease contrasts with an increase in epidermal growth factor receptor (EGFR) mRNA. Both effects were selectively achieved by TNF-alpha or -beta, whereas interferon alpha or gamma or transforming growth factor beta showed no such effects. The inverse regulatory effects of TNF on ERBB2 and EGFR mRNA levels were evoked by different signaling pathways of p55 TNF receptors. The TNF-mediated ERBB2 mRNA decrease was followed by a reduction in protein. Four of five pancreatic tumor cell lines exhibited this down-regulation. This decrease of ERBB2 is a singular example of a modulation of this growth factor receptor by TNF. Overexpression of ERBB2 has been reported to cause resistance to TNF and other cytotoxic cytokines. In our study we show that the TNF-mediated down-regulation of ERBB2 in pancreatic tumor cells is accompanied by an increase in growth inhibition at low doses of TNF. The simultaneous alteration of the ERBB2/EGFR balance by TNF represents a striking model of cytokine receptor transregulation in the growth control of malignant pancreatic epithelial cells.
Insights
Tumor necrosis factor (TNF) down-regulates ERBB2 in pancreatic cancer cells, increasing sensitivity to TNF. This cytokine receptor transregulation impacts malignant cell growth.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Overexpression of ERBB2 is linked to resistance to cytotoxic cytokines like TNF.
- Pancreatic tumor cells are a significant area of cancer research.
Purpose of the Study:
- To investigate the effect of TNF on ERBB2 and EGFR mRNA and protein expression in pancreatic tumor cells.
- To understand the role of TNF-mediated ERBB2 down-regulation in pancreatic cancer growth control.
Main Methods:
- Treatment of pancreatic tumor cell lines with recombinant human TNF-alpha and TNF-beta.
- Analysis of ERBB2 and EGFR mRNA and protein levels using molecular biology techniques.
Main Results:
- TNF selectively decreased ERBB2 mRNA and protein expression, while increasing EGFR mRNA.
- Four out of five pancreatic tumor cell lines showed TNF-mediated ERBB2 down-regulation.
- Down-regulation of ERBB2 correlated with increased growth inhibition by low doses of TNF.
Conclusions:
- TNF plays a unique role in modulating ERBB2 expression in pancreatic cancer.
- The inverse regulation of ERBB2 and EGFR by TNF offers a novel model for cytokine receptor transregulation in pancreatic cancer.
- Targeting ERBB2/EGFR balance via TNF may enhance therapeutic strategies for pancreatic cancer.