Artikel
The Rap1/B-Raf signaling complex is a putative therapeutic target in neuroendocrine tumors of the digestive tract
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Veröffentlicht: | 20. März 2006 |
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Gliederung
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Background: Molecular pathogenesis of digestive neuroendocrine tumors (dNETS) is largely unknown. Recently, the serine-threonine kinase B-Raf was identified as an oncogene in endocrine cancer such as thyroid carcinoma. In endocrine cells, the small G-protein Rap1 stimulates mitogen-activated protein kinase (MAPK) signaling by activating B-Raf.
Aims: We examined the contribution of Rap1 and B-Raf to pathogenesis of dNETS by investigating expression of Rap1 and B-Raf in dNETS and their contribution to MAPK signaling in neuroendocrine cell lines. In addition, we explored the benefit of suppressing B-Raf kinase by the recently developed inhibitor BAY 43-9006 (Sorafenib) on growth as well as apoptosis and MAPK activation in neuroendocrine cell lines.
Methods and results: Expression of Rap1 and B-Raf in dNETS (19 insulinomas, 15 carcinoid tumors and 10 gastrinomas) was examined by immunohistochemistry, which revealed that Rap1 and B-Raf were highly prevalent in the majority of dNETs. Overexpression of Rap1 and B-Raf activated MAPK extra-cellular dependent kinase (ERK) ERK-2 and ERK-dependent transcription factor Elk-1 in neuroendocrine cell lines Bon and INS-1. Suppression of B-Raf by BAY43-9006 (Sorafenib) inhibited growth and induced apoptosis in Bon and INS-1 cells. In addition, BAY 43-9006 suppressed phosphorylation of MAPK ERK1/2 and its upstream kinase MEK1/2 in Bon and INS-1 cells.
Conclusions: These results indicate that Rap1/B-Raf signaling may contribute to pathogenesis of dNETs and provides a promising molecular target for treatment of dNETs.