Signal transduction of somatostatin receptors negatively controlling cell proliferation

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Abstract

Somatostatin acts as an inhibitory peptide of various secretory and proliferative responses. Its effects are mediated by a family of G-protein-coupled receptors (sst1-5) that can couple to diverse signal transduction pathways such as inhibition of adenylate cyclase and guanylate cyclase, modulation of ionic conductance channels, and protein dephosphorylation. The five receptors bind the natural peptide with high affinity but only sst2, sst5 and sst3 bind the short synthetic analogues. Somatostatin negatively regulates the growth of various normal and tumour cells. This effect is mediated indirectly through inhibition of secretion of growth-promoting factors, angiogenesis and modulation of the immune system. Somatostatin can also act directly through sst receptors present on target cells. The five receptors are expressed in various normal and tumour cells, the expression of each receptor being receptor subtype and cell type specific. According to the receptor subtypes, distinct signal transduction pathways are involved in the antiproliferative action of somatostatin. Sst1, 4 and 5 modulate the MAP kinase pathway and induce G1 cell cycle arrest. Sst3 and sst2 promote apoptosis by p53-dependent and -independent mechanisms, respectively.

Introduction

Somatostatin acts on various targets including the brain, pituitary, pancreas, gut, adrenals, thyroid, kidney and immune system to regulate a variety of physiological functions. Its actions include inhibition of endocrine and exocrine secretions, modulation of neurotransmission, motor and cognitive functions, inhibition of intestinal motility, absorption of nutrients and ions, vascular contractility and cell proliferation. The biological effects of somatostatin are mediated via high affinity plasma membrane receptors which are widely distributed throughout many tissues ranging from the central nervous system to the pancreas and gut, and also in pituitary, kidney, thyroid, lung and immune cells [14], [23].

Due to the short half-life of natural somatostatin peptides, many somatostatin peptide analogues have been synthesised. Among them, octreotide (SMS 201-995), lanreotide (BIM 23014) and vapreotide (RC-160) are in clinical use for the medical treatment of acromegaly and neuroendocrine tumours.

Compelling evidence has implicated somatostatin in the inhibition of the growth and development of various normal and tumour cells. Thus, somatostatin analogues show antineoplastic activity in a variety of experimental models in vivo and in vitro [40], [50]. Somatostatin receptors are expressed in a large variety of human tumours and somatostatin analogue treatment induces the shrinkage of pituitary [29] and the stabilization of neuroendocrine tumour progression [3]. However, the clinical implications of the presence of somatostatin receptors in tumours for diagnostic and therapeutic purposes will need to define the physiological role of each receptor subtype expressed in the tumours with respect to its antisecretory and antiproliferative properties.

Section snippets

Somatostatin receptor family

To date, five receptors subtypes, sst1-sst5, have been cloned. Human sst subtypes are encoded by 5 genes localized on separate chromosomes. Four of these genes are intronless in their coding region, the exception being sst2 which is alternatively spliced in rodents to generate two isoforms named sst2A and sst2B which diverge in their C-terminal sequence. The sst subtypes belong to the family of G-protein coupled receptors with seven transmembrane spanning domains and present a high degree of

Indirect effects of somatostatin on cell growth

Indirect effects of somatostatin on tumour growth may be the result of inhibition of secretion of growth-promoting hormones and growth factors which stimulate the growth of various types of cancer. For example, insulin-like growth factor-1 (IGF-1) which is produced by hepatocytes through GH-dependent and -independent mechanisms is an important modulator of many neoplasms [25] and octreotide negatively controls serum IGF-1 level as a result of an effect on GH secretion, probably via sst2 and

Direct effect of somatostatin on cells

Somatostatin directly inhibits cell growth by interacting with specific somatostatin receptors located on target cells. Somatostatin receptors are present in various normal and cancer cells [31]. Analysis of sst mRNAs demonstrate that human tumours from neuroendocrine and gastroenteropancreatic origin, brain tumours (gliomas and meningiomas), prostate, lung and breast tumours express sst mRNA, each tumour expressing more than one subtype and sst2 being the most frequently expressed [31], [36].

Conclusion

The five somatostatin receptors can be involved in the growth inhibitory effect of somatostatin and analogues and this property may be relevant for the analogue therapy of tumours which express somatostatin receptors. However, most of studies of the antiproliferative effect of somatostatin receptor subtypes have been conducted in vitro, on recombinant cells. The development of specific antibodies, agonists and antagonists as well as gene knockout models will help to define in vivo, the role of

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