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

Surgery. 2004 Dec;136(6):1297-302. doi: 10.1016/j.surg.2004.06.061.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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

Substances

  • Chromogranin A
  • Chromogranins
  • Insulin-Like Growth Factor I
  • Proto-Oncogene Proteins c-raf
  • MAP Kinase Kinase 1