Role of somatostatin receptor 1 and 5 on epidermal growth factor receptor mediated signaling

Abstract

Epidermal growth factor (EGF) regulates normal and tumor cell proliferation via epidermal growth factor receptor (EGFR) phosphorylation, homo- or heterodimerization and activation of mitogen-activated protein kinases (MAPKs) and PI3K/AKT cell survival pathways. In contrast, SST via activation of five different receptor subtypes inhibits cell proliferation and has been potential target in tumor treatment. To gain further insight for the effect of SSTRs on EGFR activated signaling, we determine the role of SSTR1 and SSTR1/5 in human embryonic kidney (HEK) 293 cells. We here demonstrate that cells transfected with SSTR1 or SSTR1/5 negatively regulates EGF mediated effects attributed to the inhibition of EGFR phosphorylation, MAPKs as well as the cell survival signaling. Furthermore, SSTR effects were significantly enhanced in cells when EGFR was knock down using siRNA or treated with selective antagonist (AG1478). Most importantly, the presence of SSTR in addition to modulating signaling pathways leads to the dissociation of the constitutive and EGF induced heteromeric complex of EGFR/ErbB2. Furthermore, cells cotransfected with SSTR1/5 display pronounced effect of SST on the signaling and dissociation of the EGFR/ErbB2 heteromeric complex than the cells expressing SSTR1 alone. Taken together this study provides the first evidence that the presence of SSTR controls EGF mediated cell survival pathway via dissociation of ErbB heteromeric complex. We propose that the activation of SSTR and blockade of EGFR might serve novel therapeutic approach in inhibition of tumor proliferation.

Cross-talk and modulation of signaling between somatostatin and growth factor receptors

“…These studies directly support the possible interactions between ErbBs and SSTRs and its consequences on cell proliferation and signal transduction pathways [80]. With this concept in mind, we recently described that SSTR1 and SSTR5 functionally interact with EGFR in heteromeric complex in breast cancer cells including MCF-7 cells and MDA-MB231 cells [41][42][43]. Because, in tumor cells, all ErbBs and SSTR subtypes are expressed and respond to common ligands, it was difficult to delineate the role of individual receptors.…”

“…Because, in tumor cells, all ErbBs and SSTR subtypes are expressed and respond to common ligands, it was difficult to delineate the role of individual receptors. Kharmate et al [41,42] recently described the cross-talk between SSTR and ErbB subtypes in HEK-293 cells expressing ErbBs endogenously and transfected with SSTR subtypes. As discussed in next section of this review SSTR1 and SSTR5 mono-or cotransfected cells displayed receptor-specific role on EGF-mediated signal transduction pathways.…”

“…With respect to the formation of SSTR2 and D2R heterodimers, dopamine affinity was increased and SSTR2 functions remained unchanged [35]. Furthermore, recent studies have also described that SSTR1 and SSTR5 functionally interact with adrenergic and growth factor receptors with significant changes in receptor coupling to adenylyl cyclase and signaling in receptor specific manner [39][40][41][42][43]. Whether, the activation of two receptors in the presence of receptor-specific agonist also elicit similar effects in cells expressing these receptor endogenously is largely elusive.…”

“…SSTR subtypes not only heterodimerize within the family but does so with other members of GPCR family like dopamine, opioid, adrenergic, and growth factor receptors [28,30,31,[34][35][36][37][38][39][40][41][42][43]. In addition to displaying receptorspecific dimerization, SSTR subtypes have shown great diversity upon heterodimerization as well.…”

Translation of Molecular Pathways into Clinical Trials of Neuroendocrine Tumors

“…These targets have also been identified to be involved in pathogenesis and tumor growth of NET [13,14]. Ligand binding and potential receptor mutations may lead to activation of signaling pathways that frequently overlap or may be linked [15,16]. Potential therapeutic targets may therefore comprise receptors, receptor tyrosine kinases, ligands, intracellular kinases or enzymes.…”