Somatostatin and Epidermal Growth Factor Receptors: Implications in Breast Cancer

Despite several advances, the underlying mechanism of complexity of breast cancer progression still remains elusive. In addition to the genetic predisposition, several growth factor receptors including insulin growth factor receptor (IGF), platelet derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) relaying proliferative signals are accountable for disease progression. Epidermal growth factor receptors (EGFRs, or commonly known as ErbBs), members of the receptor tyrosine kinase family (RTKs), play a central role in tumor growth, progression and metastatic disease. Typically, agonist dependent activation of EGFR results in receptor phosphorylation, homo- and/or heterodimerization and modulation of signaling pathways leading to cell proliferation, survival and metastasis. Targeting one or multiple steps in EGFR-mediated tumor progression may serve as a better approach in drug therapies. Unlike EGFRs, G-protein coupled somatostatin receptors (SSTRs) have been recognized as negative regulators of breast tumors. The activation of SSTRs modulates downstream signaling responsible for tumor growth and consequent cytostatic or cytotoxic effects on tumor proliferation. SSTR subtypes are well characterized to form homo-and/or heterodimers within the same family as well as with other GPCRs. Clinically, the chimeric molecule targeting both SSTR5 and dopamine receptors (specifically dopamine receptor 2) is in use for the treatment of pituitary tumors. This review describes the interplay between SSTRs and EGFR and the potential role of such cross talk in attenuation of EGFR-mediated signaling pathways involved in tumorigenesis. Furthermore, recent findings supporting the role of SSTR in EGFR-mediated signaling in tumor biology are discussed in detail

Differential regulation of somatostatin receptors 1 and 2 mRNA and protein expression by tamoxifen and estradiol in breast cancer cells

Somatostatin (SST) inhibition of hormone hypersecretion from tumors is mediated by somatostatin receptors (SSTRs). SSTRs also play an important role in controlling tumor growth through specific antiproliferative actions. These receptors are well expressed in numerous normal and tumor tissues and are susceptible to regulation by a variety of factors. Estradiol, a potent trophic and mitogenic hormone in its target tissues, is known to modulate the expression of SST and its receptors. Accordingly, in the present study, we determined the effects of tamoxifen, a selective estrogen receptor (ER) modulator (SERM), and estradiol on SSTR1 and SSTR2 expression at the mRNA and protein levels in ER-positive and -negative breast cancer cells. We found that SSTR1 was upregulated by tamoxifen in a dose-dependent manner but no effect was seen with estradiol. In contrast, SSTR2 was upregulated by both tamoxifen and estradiol. Combined treatment caused suppression of SSTR1 below control levels but had no significant effect on SSTR2. Treatment with SSTR1-specific agonist was significantly more effective in suppressing cell proliferation of cells pre-treated with tamoxifen. Taking these data into consideration, we suggest that tamoxifen and estradiol exert variable effects on SSTR1 and SSTR2 mRNA and protein expression and distributional pattern of the receptors. These changes are cell subtype-specific and affect the ability of SSTR agonists to inhibit cell proliferation

Somatostatin Receptor 1 and 5 Double Knockout Mice Mimic Neurochemical Changes of Huntington's Disease Transgenic Mice

Selective degeneration of medium spiny neurons and preservation of medium sized aspiny interneurons in striatum has been implicated in excitotoxicity and pathophysiology of Huntington's disease (HD). However, the molecular mechanism for the selective sparing of medium sized aspiny neurons and vulnerability of projection neurons is still elusive. The pathological characteristic of HD is an extensive reduction of the striatal mass, affecting caudate putamen. Somatostatin (SST) positive neurons are selectively spared in HD and Quinolinic acid/N-methyl-D-aspartic acid induced excitotoxicity, mimic the model of HD. SST plays neuroprotective role in excitotoxicity and the biological effects of SST are mediated by five somatostatin receptor subtypes (SSTR1-5). and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidylinositol 3-kinases were strain specific. SSTR1/5 appears to be important in regulating NMDARs, DARPP-32 and signaling molecules in similar fashion as seen in HD transgenic mice.This is the first comprehensive description of disease related changes upon ablation of G- protein coupled receptor gene. Our results indicate that SST and SSTRs might play an important role in regulation of neurodegeneration and targeting this pathway can provide a novel insight in understanding the pathophysiology of Huntington's disease

Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System

The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.Pharmaceutical Sciences, Faculty ofReviewedFacult

Colocalization of somatostatin receptors and epidermal growth factor receptors in breast cancer cells

Background: Somatostatin receptor (SSTR) expression is positively correlated with tumor size and inversely correlated with epidermal growth factor receptor (ErbB) levels and tumor differentiation. In the present study, we compared SSTR1-5 and ErbB1-4 mRNA and protein expression in two breast cancer cell lines: MCF-7 (ER+) and MDA-MB-231 (ERα-). Results All five SSTRs and four ErbBs were variably expressed as both cell surface and cytoplasmic proteins. In both cell lines, SSTR4 and SSTR1 were highly expressed, followed by SSTR2 and SSTR5 with SSTR3 being the least expressed subtype, at the protein level. ErbBs were variably expressed with ErbB1 as the predominant subtype in both cell lines. ErbB1 is followed by ErbB3, ErbB2 and ErbB4 in MCF-7 at both the protein and mRNA levels. In MDA-MB-231 cells, ErbB1 is followed by ErbB2, ErbB4 and ErbB3. Our results indicate significant correlations at the level of mRNA and protein expression in a cell and receptor-specific manner. Using indirect immunofluorescence, we found that, in MCF-7 cells, SSTR5 was the most prominent subtype coexpressed with ErbBs followed by SSTR3, SSTR4, SSTR1 and SSTR2, respectively. In MDA-MB-231 cells, SSTR1 colocalized strongly with ErbBs followed by SSTR5, SSTR4, SSTR3 and SSTR2. ErbBs displayed higher levels of colocalization amongst themselves in MCF-7 cells than in MDA-MB-231 cells. Conclusion These findings may explain the poor response to endocrine therapy in ER-cancer. Differential distribution of SSTR subtypes with ErbBs in breast cancer cells in a receptor-specific manner may be considered as a novel diagnosis for breast tumors.Pharmaceutical Sciences, Faculty ofOther UBCNon UBCReviewedFacult

Role of Somatostatin in the Regulation of Central and Peripheral Factors of Satiety and Obesity

Obesity is one of the major social and health problems globally and often associated with various other pathological conditions. In addition to unregulated eating behaviour, circulating peptide-mediated hormonal secretion and signaling pathways play a critical role in food intake induced obesity. Amongst the many peptides involved in the regulation of food-seeking behaviour, somatostatin (SST) is the one which plays a determinant role in the complex process of appetite. SST is involved in the regulation of release and secretion of other peptides, neuronal integrity, and hormonal regulation. Based on past and recent studies, SST might serve as a bridge between central and peripheral tissues with a significant impact on obesity-associated with food intake behaviour and energy expenditure. Here, we present a comprehensive review describing the role of SST in the modulation of multiple central and peripheral signaling molecules. In addition, we highlight recent progress and contribution of SST and its receptors in food-seeking behaviour, obesity (orexigenic), and satiety (anorexigenic) associated pathways and mechanism.Pharmaceutical Sciences, Faculty ofReviewedFacult

Pathophysiology of GPCR Homo- and Heterodimerization: Special Emphasis on Somatostatin Receptors

G-protein coupled receptors (GPCRs) are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules activating distinct downstream signaling pathways. All GPCRs share common structural features including an extracellular N-terminal, seven-transmembrane domains (TMs) linked by extracellular/intracellular loops and the C-terminal tail. Recent studies have shown that most GPCRs function as dimers (homo- and/or heterodimers) or even higher order of oligomers. Protein-protein interaction among GPCRs and other receptor proteins play a critical role in the modulation of receptor pharmacology and functions. Although ~50% of the current drugs available in the market target GPCRs, still many GPCRs remain unexplored as potential therapeutic targets, opening immense possibility to discover the role of GPCRs in pathophysiological conditions. This review explores the existing information and future possibilities of GPCRs as tools in clinical pharmacology and is specifically focused for the role of somatostatin receptors (SSTRs) in pathophysiology of diseases and as the potential candidate for drug discovery.Pharmaceutical Sciences, Faculty ofReviewedFacult

Somatostatin-Mediated Regulation of Retinoic Acid-Induced Differentiation of SH-SY5Y Cells: Neurotransmitters Phenotype Characterization

During brain development, neurite formation plays a critical role in neuronal communication and cognitive function. In the present study, we compared developmental changes in the expression of crucial markers that govern the functional activity of neurons, including somatostatin (SST), choline acetyltransferase (ChAT), tyrosine hydroxylase (TH), brain nitric oxide synthase (bNOS), gamma-aminobutyric acid (GABA), glutamic acid decarboxylase (GAD-65) and synaptic vesicle protein synaptophysin (SYP) in non-differentiated and retinoic acid (RA)-induced differentiated SH-SY5Y cells. We further determined the role of SST in regulating subcellular distribution and expression of neurotransmitters. Our results indicate that SST potentiates RA-induced differentiation of SH-SY5Y cells and involves regulating the subcellular distribution and expression of neurotransmitter markers and synaptophysin translocation to neurites in a time-dependent manner, anticipating the therapeutic implication of SST in neurodegeneration.Pharmaceutical Sciences, Faculty ofReviewedFacult