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Am J Physiol Gastrointest Liver Physiol 285: G245-G254, 2003; doi:10.1152/ajpgi.00420.2002
0193-1857/03 $5.00
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TRANSLATIONAL PHYSIOLOGY

Raf-1 activation suppresses neuroendocrine marker and hormone levels in human gastrointestinal carcinoid cells

Rebecca S. Sippel, Jennifer E. Carpenter, Muthusamy Kunnimalaiyaan, Sara Lagerholm, and Herbert Chen

Department of Surgery, The University of Wisconsin Medical School, and the University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792

Submitted 26 September 2002 ; accepted in final form 3 April 2003

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.

MAP kinase; signal transduction; neuroendocrine tumors


Address for reprint requests and other correspondence: H. Chen, Dept. of Surgery, Univ. of Wisconsin Medical School, H4/750 Clinical Science Center, 600 Highland Ave., Madison, WI 53792 (E-mail: chen{at}surgery.wisc.edu).




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