Raf-1 activation suppresses neuroendocrine marker and hormone levels in human gastrointestinal carcinoid cells. Am J Physiol Gastrointest Liver Physiol 2003 Aug;285(2):G245-54
Date
07/10/2003Pubmed ID
12851216DOI
10.1152/ajpgi.00420.2002Scopus ID
2-s2.0-0038442134 (requires institutional sign-in at Scopus site) 78 CitationsAbstract
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.
Author List
Sippel RS, Carpenter JE, Kunnimalaiyaan M, Lagerholm S, Chen HMESH terms used to index this publication - Major topics in bold
Biomarkers, TumorCarcinoid Tumor
Cell Division
Chromogranin A
Chromogranins
Enzyme Activation
Enzyme Inhibitors
Humans
MAP Kinase Kinase Kinase 1
Microscopy, Electron
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases
Neurosecretory Systems
Pancreatic Neoplasms
Phosphorylation
Proto-Oncogene Proteins c-raf
Secretory Vesicles
Serotonin
Signal Transduction
Synaptophysin
Transfection
Tumor Cells, Cultured
