Pancreatic stellate/myofibroblast cells express G-protein-coupled melatonin receptor 1

Abstract

In chronic pancreatitis and pancreatic cancer, progressive fibrosis with the accumulation of extracellular matrix occurs. The main extracellular matrix-producing cell types are retinoid-storing pancreatic stellate cells (PSCs) of mesenchymal origin. Similar to liver stellate cells, quiescent PSCs undergo activation and acquire a myofibroblast-like phenotype in response to pro-fibrogenic mediators (reactive oxygen species, cytokines and toxic metabolites). Activated PSCs differ in their differentiation stage and are characterized by the expression of glial fibrillary-acidic protein, alpha-smooth muscle actin, and nestin. As G-protein-coupled receptors were described to regulate PSC differentiation, we investigated tissue samples from patients with pancreatitis and ductal pancreatic adenocarcinoma for the expression of G-protein-coupled melatonin receptors MT1 and MT2 by double immunofluorescence staining. We show that MT1, but not MT2, is occasionally expressed in PSCs in normal tissue, while in the diseased tissue MT1 is found at high rates in activated PSCs at all stages, and, additionally, in ductal epithelial cells. It is speculated that MT1 activation by its ligand melatonin regulates proliferation and differentiation of PSCs. Prevention of myofibroblast formation by MT1 activation could explain favourable effects of the pineal hormone melatonin on the outcome of pancreatic fibrosis in animal models.

Regulation of L1 expression and retrotransposition by melatonin and its receptor: implications for cancer risk associated with light exposure at night

“…The G-coupled melatonin receptor 1 (MT1) is widely expressed both within and outside the central nervous system (34,35). The MT1 receptor expression is increased to varying degrees in many cancers of epithelial origin, including breast, pancreatic and gallbladder cancers (36–39). Similar to melatonin production, MT1 receptor expression exhibits circadian variation (34,40).…”

Subcellular distribution of melatonin receptors in human parotid glands

“…Most of the biological functions of melatonin are thought to be mediated by the membrane receptors, melatonin 1 (MT1) and 2 (MT2). In addition to their presence in the central nervous system, melatonin receptors are found in several peripheral structures, such as duodenal enterocytes (Sj€ oblom & Flemstr€ om, 2003Slominski et al 2012), gall-bladder epithelium (Aust et al 2004), the exocrine pancreas (Aust et al 2008), the endocrine pancreas (Mulder et al 2009), the skin (Slominski et al 2005(Slominski et al , 2012 and the parotid gland (Cevik Aras & Ekstr€ om, 2008). In humans, using light microscopy, the presence of MT1-receptor immunoreactivity was reported in parotid glands (Aneiros-Fernandez et al 2012;Arias-Santiago et al 2012) but not in submandibular glands (Shimozuma et al 2011).…”

LINE-1 activity as molecular basis for genomic instability associated with light exposure at night

“…[53][54][55][56][57] The levels of melatonin receptor expression vary significantly between normal and cancer cells, with most cancers expressing higher (and only a few lower) levels of the MT1 receptor than their corresponding normal tissues. [58][59][60][61][62] This suggests that cancer cells may be hypersensitive to melatonin suppression relative to their normal counterparts. The tissue-specific differences in the levels of melatonin receptor expression 61 suggest a possibility that various tissues may be experiencing different levels of upregulation in L1-induced damage upon LAN.…”