Insulin-like growth factor 1 signaling in human gastrointestinal carcinoid tumor cells.
Background 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. Methods 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. Results 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. Conclusions 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.
Van Gompel
Jamie Joseph
JJ
Department of Surgery, University of Wisconsin Comprehensive Cancer Center, 600 Highland Avenue, Madison, WI 53792, USA.
Chen
Herbert
H
D002276:Carcinoid Tumor / Q000503:physiopathology*; D045744:Cell Line, Tumor; D053379:Chromogranin A; D002864:Chromogranins / Q000502:physiology; D005770:Gastrointestinal Neoplasms / Q000503:physiopathology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D053379:Chromogranin A; D002864:Chromogranins; D007334:Insulin-Like Growth Factor I; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1