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Raf-1 kinase, epidermal growth factor receptors, and mutant Ras proteins in colonic carcinomas
S Eggstein1, G Manthey, T Hirsch
1Chirurgische Universitätsklinik Freiburg, Abteilung Allgemeine Chirurgie mit Poliklinik, Germany.
Abstract:
Epidermal growth factor receptors (EGFR) and ras mutations are known to play a significant role in controlling cell growth and tumor promotion. Both of them transmit mitogenic signals to the nucleus by activation of Raf-1 kinase. In this study, the expression of EGFR and mutant Ras proteins, and, for the first time, the expression, phosphorylation and kinase activity of Raf-1 kinase have been determined in paired samples of colorectal cancer and mucosa. The tumor and mucosa samples did not differ significantly with regard to Raf-1 kinase content and activity. A major difference between tumors and mucosa was found, however, in the phosphorylation of Raf-1. Most of the mucosa samples (13/20), but only 1/20 of the cancer samples, contained hyperphosphorylated Raf-1. EGFR were significantly (p = 0.0025) decreased in the tumors. The decreased phosphorylation of Raf-1 in colonic carcinomas could be the result of activation of Raf-1 phosphatases or inactivation of kinases phosphorylating Raf-1. New forms of treatment based on EGFR overexpression do not seem to be suitable for the majority of colonic cancers.
Insights
Colorectal cancer cells show decreased epidermal growth factor receptor (EGFR) and reduced Raf-1 kinase phosphorylation compared to normal tissue. This suggests EGFR-targeted therapies may not benefit all colon cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Epidermal growth factor receptors (EGFR) and ras mutations are key regulators of cell growth and tumor promotion.
- EGFR and Ras signaling pathways converge on Raf-1 kinase to transmit mitogenic signals to the nucleus.
Purpose of the Study:
- To investigate the expression, phosphorylation, and kinase activity of Raf-1 in paired colorectal cancer and adjacent mucosa samples.
- To compare the levels of EGFR and Ras mutations between tumor and normal colorectal tissues.
Main Methods:
- Analysis of paired colorectal cancer and mucosa samples.
- Determination of EGFR and Ras protein expression.
- Assessment of Raf-1 kinase expression, phosphorylation status, and kinase activity.
Main Results:
- No significant differences were observed in Raf-1 kinase content or activity between tumor and mucosa samples.
- A significant decrease in EGFR expression was found in tumors compared to mucosa (p = 0.0025).
- Hyperphosphorylated Raf-1 was prevalent in mucosa (13/20 samples) but rare in tumors (1/20 samples).
Conclusions:
- Decreased Raf-1 phosphorylation in colon carcinomas may result from altered phosphatase or kinase activity.
- Targeted therapies based on EGFR overexpression may not be effective for most colorectal cancer patients due to decreased EGFR levels.