Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells

Carcinoid tumors are predominantly found in the gastrointestinal tract and are characterized by hypersecretion of various substances, including bioami nes and neuropeptides, leading to functional tumor disease. Here, we demons trate that human BON carcinoid tumor cells express functionally active insu lin-like growth factor-I (IGF-I) receptors and secrete IGF-I, suggesting an autocrine action of this growth factor. The IGF-I receptor was functionall y active. IGF-I stimulated phosphatidylinositol 3-kinase (PIS-kinase), p70 SG kinase (p70(s6k)), and extracellular signal-regulated kinase 2 activity in BON cells. Furthermore, immunoneutralization of endogenously released IG F-I markedly reduced the high basal activity of p70(s6k) and extracellular signal-regulated kinase 2 in serum-starved BON cells. Exogenously added IGF -I induced a marked increase in chromogranin A secretion, a marker protein for neuroendocrine secretion, by a process that was largely dependent on PI 3-kinase activity. In addition, immunoneutralization of endogenously releas ed IGF-I markedly reduced basal chromogranin A release by BON cells. Thus, the autocrine IGF-I loop regulates basal neuroendocrine secretion in BON ce lls. Next, we investigated the role of IGF-I as a growth promoting agent fo r BON cells. Our data demonstrate that IGF-I stimulates anchorage-dependent and anchorage-independent growth of BON cells by a pathway that involves P IS-kinase, mammalian target of rapamycin/p70(s6k), and mitogen-activated pr otein kinase kinase 1 activity. Interestingly; mitogen-activated protein ki nase kinase 1 activity mas less important for anchorage-independent growth of BON cells. Endogenously released IGF-I was found to be largely responsib le for autonomous growth of BON cells in serum-free medium and for the cons titutive expression of cyclin D1 in these cells. In conclusion, IGF-I is a major autocrine regulator of neuroendocrine secretion and growth of human B ON neuroendocrine tumor cells. Because our data also demonstrate that a sig nificant proportion of neuroendocrine tumors express the IGF-I receptor and its ligand, interference with this pathway could be useful in the treatmen t of hypersecretion syndromes and growth of human neuroendocrine tumors.