Insulin-like growth factor 1 signaling in human gastrointestinal carcinoid tumor cells

• Published in: Surgery Vol. 136; no. 6; pp. 1297 - 1302
• Main Authors: Van Gompel, Jamie Joseph, Chen, Herbert
• Format: Journal Article
• Language: English
• Published: United States Mosby, Inc 01.12.2004
• Subjects: Carcinoid Tumor - physiopathology; Cell Line, Tumor; Chromogranin A; Chromogranins - physiology; Gastrointestinal Neoplasms - physiopathology; Humans; Insulin-Like Growth Factor I - physiology; MAP Kinase Kinase 1 - physiology; Proto-Oncogene Proteins c-raf - physiology; Signal Transduction - physiology
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/j.surg.2004.06.061

Insulin-like growth factor 1 (IGF-1) is an autocrine regulator of carcinoid tumors. Blockade of IGF-1 signaling has been proposed as a therapeutic target in the treatment of patients with carcinoid syndrome. We hypothesized that the induction of parallel raf-1/MEK1 pathways will block IGF-1–mediated chromogranin A (CgA) maintenance. Human gastrointestinal carcinoid tumor cells (BON) were treated with IGF-1 (0-500 ng/mL). Raf-1/MEK1 activation was achieved with an estrogen-inducible raf-1 vector that was transduced into BON cells. Activation of IGF-1/raf-1 pathways was determined by phosphorylation of downstream targets p70s6 and ERK1/2. The secreted and intercellular levels of CgA were measured in conditioned media and whole cell extracts by Western and enzyme-linked immunosorbent assay analysis. IGF-1 and raf-1 pathways were activated successfully in BON cells, as shown by high levels of phosphorylated p70s6 and phosphorylated ERK1/2, respectively. Treatment of BON cells with IGF-1 stimulated the release of CgA, while high intracellular CgA levels were maintained. The activation of raf-1/MEK1 reversed the effect of IGF-1 treatment by the depletion of intracellular CgA. The induction of the raf-1/MEK1 pathway blocks IGF-1–mediated intracellular neuroendocrine hormone regulation. Therefore, raf-1/MEK1 activation may be a viable method to block IGF-1–mediated cellular effects and serve as a therapeutic target in gastrointestinal carcinoid tumors.