The Synergistic Effects of Octreotide and Raf-1 Activation in Pancreatic Neuroendocrine Cells
Gillis, Holly Catherine
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Carcinoids are neuroendocrine tumors (NETs) that produce bioactive substances such as serotonin (5-HT) and chromogranin A (CgA), causing carcinoid syndrome. Besides surgery, limited treatments are available to patients with carcinoid tumors and carcinoid syndrome. Octreotide effectively manages carcinoid syndrome by inhibiting secretion of bioactive hormones. Activation of the Raf-1 pathway in carcinoid cells suppresses NET markers, as well as cellular proliferation. In this study, we hypothesize that treatment of carcinoid cancer cells with octreotide and Raf-1 activation may act synergistically to inhibit NE tumor markers and suppress cellular growth. Human pancreatic carcinoid tumor cells stably transduced with an estradiol-inducible Raf-1 construct were treated with varying amounts of B-estradiol to activate the Raf-1 signaling pathway, while an equivalent dose of ethanol, was used to treat control cells. Raf-1 activated and control cells were subsequently treated with up to 30 uM of the somatostatin analogue, octreotide. Western analysis demonstrated activation of the Raf-1 pathway and decreases in NE tumor markers. Tumor cell proliferation was measured by the methylthiazolyldiphenyl-tetrazolium (MTT) bromide rapid colorimetric assay. Bestradiol treatment resulted phosphorylation of ERK1/2, indicating activation of the Raf-1 signaling pathway. Treatment with 30 uM octreotide alone inhibited carcinoid cell growth by only 13%, but the addition of Raf-1 activation resulted in a 22%reduction and induction of Raf-1 also led to a marked reduction in NE hormone levels showing synergistic growth inhibition. These data emphasize the need to further explore combination therapies involving pharmacologic Raf-1 activation and octreotide therapy as potential options for patients with disseminated carcinoid disease.