Rap1/B-Raf signaling is activated in neuroendocrine tumors of the digestive tract and Raf kinase inhibition constitutes a putative therapeutic target.
OBJECTIVE
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. We examined the expression of Rap1 and B-Raf in dNETs and their contribution to MAPK signaling in neuroendocrine cell lines. In addition, we explored the effect of suppressing B-Raf kinase by the recently developed inhibitor BAY43-9006 (Sorafinib) on growth, apoptosis and MAPK activation neuroendocrine cell lines.


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 extracellular 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 inhibited growth and induced apoptosis in Bon and INS-1 cells. In addition, BAY43-9006 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 molecular target for treatment of dNETs.
Karhoff
Dorothee
D
Department of Internal Medicine, Division of Gastroenterology and Endocrinology, Philipps University Marburg, Marburg, Germany.
Sauer
Susanne
S
Schrader
Jörg
J
Arnold
Rudolf
R
Fendrich
Volker
V
Bartsch
Detlef K
DK
Hörsch
Dieter
D
D001557:Benzenesulfonates / Q000494:pharmacology; D004067:Digestive System Neoplasms / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000077157:Sorafenib; D013778:Tetrazolium Salts; D013844:Thiazoles; D048490:raf Kinases / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D001557:Benzenesulfonates; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D011725:Pyridines; D013778:Tetrazolium Salts; D013844:Thiazoles; D009536:Niacinamide; D000077157:Sorafenib; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D020827:rap1 GTP-Binding Proteins; C022616:thiazolyl blue