Rap1/B-Raf signaling is activated in neuroendocrine tumors of the digestive tract and Raf kinase inhibition constitutes a putative therapeutic target.
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Rap1/B-Raf signaling is activated in neuroendocrine tumors of the digestive tract and Raf kinase inhibition constitutes a putative therapeutic target. / Karhoff, Dorothee; Sauer, Susanne; Schrader, Jörg; Arnold, Rudolf; Fendrich, Volker; Bartsch, Detlef K; Hörsch, Dieter.
In: NEUROENDOCRINOLOGY, Vol. 85, No. 1, 1, 2007, p. 45-53.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Rap1/B-Raf signaling is activated in neuroendocrine tumors of the digestive tract and Raf kinase inhibition constitutes a putative therapeutic target.
AU - Karhoff, Dorothee
AU - Sauer, Susanne
AU - Schrader, Jörg
AU - Arnold, Rudolf
AU - Fendrich, Volker
AU - Bartsch, Detlef K
AU - Hörsch, Dieter
PY - 2007
Y1 - 2007
N2 - 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. 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 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. CONCLUSION: These results indicate that Rap1-B-Raf signaling may contribute to pathogenesis of dNETs and provides a molecular target for treatment of dNETs.
AB - 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. 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 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. CONCLUSION: These results indicate that Rap1-B-Raf signaling may contribute to pathogenesis of dNETs and provides a molecular target for treatment of dNETs.
M3 - SCORING: Zeitschriftenaufsatz
VL - 85
SP - 45
EP - 53
JO - NEUROENDOCRINOLOGY
JF - NEUROENDOCRINOLOGY
SN - 0028-3835
IS - 1
M1 - 1
ER -
