Abstract
Gastrointestinal carcinoid cells secrete multiple neuroendocrine markers and hormones including 5-HT and chromogranin A. The intracellular signaling pathways that regulate production of bioactive molecules are not completely understood. Our aim was to determine whether activation of the raf-1/MEK/MAPK signal transduction pathway in carcinoid cells could modulate production of neuroendocrine markers and hormones. Human pancreatic carcinoid cells (BON) were stably transduced with an estrogen-inducible raf-1 construct creating BON-raf cells. Activation of raf-1 in BON-raf cells led to a marked induction of phosphorylated MEK and ERK1/2 within 48 h. Importantly, raf-1 activation resulted in morphological changes accompanied by a marked decrease in neuroendocrine secretory granules by electronmicroscopy. Moreover, induction of raf-1 in BON-raf cells led to significant reductions in 5-HT, chromogranin A, and synaptophysin levels. Furthermore, treatment of BON-raf cells with MEK inhibitors PD-98059 and U-0126 blocked raf-1-mediated morphological changes and hormone suppression but not ERK1/2 phosphorylation. These results show that raf-1 induction suppresses neuroendocrine marker and hormone production in human gastrointestinal carcinoid cells via a pathway dependent on MEK activation.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Biomarkers, Tumor / analysis*
-
Carcinoid Tumor / chemistry
-
Carcinoid Tumor / enzymology*
-
Carcinoid Tumor / ultrastructure
-
Cell Division
-
Chromogranin A
-
Chromogranins / analysis
-
Enzyme Activation
-
Enzyme Inhibitors / pharmacology
-
Humans
-
MAP Kinase Kinase Kinase 1*
-
Microscopy, Electron
-
Mitogen-Activated Protein Kinase 1 / metabolism
-
Mitogen-Activated Protein Kinase 3
-
Mitogen-Activated Protein Kinases / metabolism
-
Neurosecretory Systems*
-
Pancreatic Neoplasms / chemistry
-
Pancreatic Neoplasms / enzymology*
-
Pancreatic Neoplasms / ultrastructure
-
Phosphorylation
-
Protein Serine-Threonine Kinases / antagonists & inhibitors
-
Protein Serine-Threonine Kinases / metabolism
-
Proto-Oncogene Proteins c-raf / genetics
-
Proto-Oncogene Proteins c-raf / metabolism*
-
Secretory Vesicles / ultrastructure
-
Serotonin / analysis
-
Signal Transduction
-
Synaptophysin / analysis
-
Transfection
-
Tumor Cells, Cultured
Substances
-
Biomarkers, Tumor
-
Chromogranin A
-
Chromogranins
-
Enzyme Inhibitors
-
Synaptophysin
-
Serotonin
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-raf
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase Kinase 1
-
MAP3K1 protein, human