Negative Regulation of Pancreatic and Duodenal Homeobox-1 by Somatostatin Receptor Subtype 5

Abstract

Somatostatin receptor subtype 5 (SSTR5) mediates the inhibitory effect of somatostatin and its analogs on insulin expression/secretion and islet cell proliferation. We provide biochemical and genetic evidence that SSTR5 exerted its physiological actions via down-regulating pancreatic and duodenal homeobox-1 (PDX-1), a β-cell-specific homeodomain-containing transcription factor. Cotransfection of SSTR5 with PDX-1 resulted in dose-dependent inhibition of PDX-1 expression in human embryonic kidney 293 cells. SSTR5 agonist RPL-1980 inhibited PDX-1 expression and abolished glucagon-like peptide 1-stimulated PDX-1 expression in mouse insulinoma β-TC-6 cells. SSTR5 knockdown by short hairpin RNA led to increased PDX-1 expression that was accompanied by enhanced insulin secretion stimulated by high glucose in β-TC6 cells and alternated expressions of cell cycle proteins that favor cell proliferation in mouse insulinoma MIN6 cells. Quantitative RT-PCR analysis showed that cotransfected SSTR5 inhibited PDX-1 mRNA expression, whereas knockdown of SSTR5 increased PDX-1 mRNA expression. In addition, we found that cotransfected wild-type SSTR5 increased PDX-1 ubiquitination in human embryonic kidney 293 cells, whereas SSTR5 P335L, a hypofunctional single nucleotide polymorphism of SSTR5, inhibited PDX-1 ubiquitination. SSTR5 knockout resulted in increased expression of PDX-1, insulin, and proliferating cell nuclear antigen in the islets of sstr(-/-) mice. Immunohistochemistry analysis showed that SSTR5 P335L was associated with elevated expression of PDX-1 in human pancreatic neuroendocrine tumor. Taken together, our studies demonstrated that SSTR5 is a negative regulator for PDX-1 expression and that SSTR5 may mediate the inhibitory effects of somatostatin and its analogs on insulin expression/secretion and cell proliferation via down-regulating PDX-1 at both transcriptional and posttranslational levels.

The regulator of G-protein signaling RGS16 promotes insulin secretion and β-cell proliferation in rodent and human islets

“… [41] showing that SST significantly suppresses MIN6 cell growth, we show here, to our knowledge for the first time, that SST inhibits glucose-induced β-cell proliferation in human islets. This is also consistent with studies in SSTR-1 and -5 knockout mice showing that SST signaling negatively regulates β-cell proliferation and mass [42] , [43] . Importantly, our results uniquely demonstrate that the inhibitory effect of SST on β-cell proliferation is regulated by RGS16, both in mouse and human islets.…”

Somatostatin Receptor SSTR-2a Expression Is a Stronger Predictor for Survival Than Ki-67 in Pancreatic Neuroendocrine Tumors

“…Somatostatin is an endogenous peptide hormone that inhibits cellular proliferation and the secretion of certain endocrine hormones. 17 , 18 Based on this principle, somatostatin analogs, such as octreotide and lanreotide, have been used for many years for symptomatic management of functional neuroendocrine tumors. 9 The impact that somatostatin analogs have on neuroendocrine tumors relies on the expression of a range of somatostatin receptors (1–5), to which they have the highest affinity to SSTR-2a and a high affinity to SSTR-5.…”

“… 3 , 7 , 9 There is evidence to suggest that SSTR-2a and SSTR-5 expressions also influence and downregulate pancreatic carcinogenesis, angiogenesis, and initiate apoptosis. 17 , 19 , 20…”

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

“…In contrast to other SSTs, a number of studies have identified single-nucleotide polymorphisms in the human SST 5 gene that may imply potential pathophysiological functions in pancreatic NETs and other cancers ( Li et al, 2011 ; Zhou et al, 2011 , 2012 ), bipolar affective disorder ( Nyegaard et al, 2002 ), acromegaly ( Lania et al, 2008 ; Ciganoka et al, 2011 ), prostate cancer ( Hormaechea-Agulla et al, 2017 ), and in the regulation of circulating IGF-1 and IGFBP3 in prostate and breast cancer ( Gu et al, 2010 ). However, only a single SST 5 mutation associated with acromegaly has been described in a single patient ( Ballare et al, 2001 ).…”