[Show abstract][Hide abstract] ABSTRACT: Spontaneous melanoma phenotype switching is controlled by unknown environmental factors and may determine melanoma outcome and responsiveness to anti-cancer therapy. We show that Orai1 and STIM2 are highly expressed and control store operated Ca(2+) entry in human melanoma. Lower extracellular Ca(2+) or silencing of Orai1/STIM2 caused a decrease in intracellular Ca(2+) , which correlated with enhanced proliferation and increased expression of microphtalmia-associated-transcription-factor, a marker for proliferative melanoma phenotype. In contrast, the invasive and migratory potential of melanoma cells was reduced upon silencing of Orai1 and/or STIM2. Accordingly, markers for a non-proliferative, tumor-maintaining phenotype such as JARID1B and Brn2 decreased. Immunohistochemical staining of primary melanomas and lymph node metastases revealed a heterogeneous distribution of Orai1 and STIM2 with elevated expression in the invasive rim of the tumor. In summary, our results support a dynamic model in which Orai1 and STIM2 inversely control melanoma growth and invasion. Pharmacological tuning of Orai1 and particularly STIM2 might thus prevent metastatic spread and render melanomas more susceptible to conventional therapy. This article is protected by copyright. All rights reserved.
Full-text · Article · Jan 2014 · Pigment Cell & Melanoma Research
[Show abstract][Hide abstract] ABSTRACT: Four types of Ca(2+) selective ion channels are known, 10 voltage gated Ca(2+) (CaV) channels, four CatSper channels, three store operated CRAC channels (ORAI channels) and at least two members of the TRPV subfamily (TRPV5, TRPV6). Some of the other TRP channels also show some Ca(2+) selectivity like certain splice variants of TRPM3. In addition to Ca(2+) selective channels, various cation channels play an important role for Ca(2+) entry and furthermore, they may also regulate Ca(2+) entry through other channels by modulating the membrane potential or other means as outlined in this review. Of the different types of cation channels, TRP channels form one of the most prominent families of non-selective cation channels with functional relevance in electrically non-excitable and electrically excitable cell types. Among these, the seven channels of the TRPC subfamily are rather non-selective with very modest Ca(2+) selectivity, whereas in the other subfamilies, cation selectivity ranges from monovalent selectivity (i.e. TRPM4, TRPM5) to divalent selectivity (i.e. TRPM6, TRPM7) or Ca(2+) selectivity (i.e. TRPV5, TRPV6). Rather than discussing the heavily reviewed individual functions of ORAI or TRP channels, we summarize data and present models how TRP and ORAI may functionally interact to guide cellular functions. We focus on T lymphocytes representing a more ORAI-dominated tissue and skin as model system in which both ORAI and TRP channel have been reported to control relevant functions. We present several interaction models how ORAI and TRP may interfere with each other's function.
Full-text · Article · Nov 2013 · European journal of pharmacology
[Show abstract][Hide abstract] ABSTRACT: Calcium signaling is an universal mechanism of transduction and processing of information inside and between human cells. Ca2+ ions are second messengers responsible for many vital physiological functions such as proliferation, differentiation and cytokine secretion. A multitude of genes encode for proteins that form receptors, channels, transporters, pumps and chelators which control the cellular Ca2+ homeostasis. Genetic defects of some of these Ca2+ handling proteins cause, among others, impaired function of the immune system (severe combined immunodeficiency) or dyskeratosis of the skin (Morbus Darier). A lot is known about the role of Ca2+ in immune and skin cells. However, how Ca2+ signals affect inflammatory skin diseases is less clear. Therefore, the interplay between the cells of the immune system and the skin cells, in particular in cutaneous inflammation, will be summarized and discussed in the following chapter.
No preview · Article · May 2013 · Journal der Deutschen Dermatologischen Gesellschaft
[Show abstract][Hide abstract] ABSTRACT: The diagnosis of scabies is clinically not always simple without the detection of mites. Histology can be difficult, particularly without clinico-pathologic correlation. [corrected] Even after adequate antiscabies treatment the dermatological symptoms and complaints can persist and necessitate an [corrected] intensive follow-up treatment. The case example described here underlines that in consideration of the multifaceted clinical appearance and the sometimes difficult detection of mites, scabies should always be considered as a differential diagnosis in cases of persistent pruritis.
[Show abstract][Hide abstract] ABSTRACT: Die Diagnosestellung der Skabies ist klinisch ohne Milbennachweis nicht immer einfach. Das histologische Bild kann entsprechend den verschiedenen klinischen Bildern sehr mannigfaltig und ohne klinisch pathologische Korrelation entsprechend komplex zu interpretieren sein. Auch nach adäquater antiskabiöser Behandlung können der Hautbefund und die Beschwerden persistieren und eine entsprechend intensivierte Nachbehandlung erforderlich machen. Mit dem hier beschriebenen Fallbeispiel möchten wir verdeutlichen, dass in Anbetracht der vielfältigen klinischen Apparenz und des teils schwierigen Milbennachweises die Skabies bei persistierenden juckenden Dermatitiden differenzialdiagnostisch stets mit erwogen werden sollte.
[Show abstract][Hide abstract] ABSTRACT: UV radiation of the skin triggers keratinocytes to secrete endothelin-1 (ET-1) that binds to endothelin receptors on neighboring melanocytes. Melanocytes respond with a prolonged increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), which is necessary for proliferation and melanogenesis. A major fraction of the Ca(2+) signal is caused by entry through Ca(2+)-permeable channels of unknown identity in the plasma membrane. ORAI Ca(2+) channels are molecular determinants of Ca(2+) release-activated Ca(2+) (CRAC) channels and are expressed in many tissues. Here, we show that ORAI1-3 and their activating partners stromal interaction molecules 1 and 2 (STIM1 and STIM2) are expressed in human melanocytes. Although ORAI1 is the predominant ORAI isoform, STIM2 mRNA expression exceeds STIM1. Inhibition of ORAI1 by 2-aminoethoxydiphenyl borate (2-APB) or downregulation of ORAI1 by small interfering RNA (siRNA) reduced Ca(2+) entry and CRAC current amplitudes in activated melanocytes. In addition, suppression of ORAI1 caused reduction in the ET-1-induced cellular viability, melanin synthesis, and tyrosinase activity. Our results imply a role for ORAI1 channels in skin pigmentation and their potential involvement in UV-induced stress responses of the human skin.
Full-text · Article · Feb 2012 · Journal of Investigative Dermatology
[Show abstract][Hide abstract] ABSTRACT: When detected in its early stages, melanoma is a curable disease in the vast majority of patients. Once metastases occur, the prognosis of this disease worsens dramatically. Metastasis localization and tumor burden are critical determinants of survival. In 2008, an estimated 8,420 deaths due to metastatic melanoma were reported in the United States. For distant metastatic disease, the overall 10-year survival rate is less than 10% and median survival of these patients ranges between 6 and 9 months.
[Show abstract][Hide abstract] ABSTRACT: The melanocortin 1-receptor (MC1R) exhibits several variants in form of single nucleotide polymorphisms (SNPs) that are known to differentially regulate melanocyte function. However, whether and how MC1R polymorphisms also affect fibroblast function has not been investigated so far.Therefore we measured intracellular cyclic adenosine monophosphate (cAMP) concentrations and cellular proliferation upon stimulation with alpha-melanocyte stimulating hormone (α-MSH) in eight different human fibroblast and melanocyte cell lines with wild type and different MC1R SNPs.We found that fibroblasts, as well as melanocytes, show differences in MC1R function depending on the MC1R genotype. MC1R stimulation with α-MSH in wild type (MC1R(wt)) melanocytes results in an increase of intracellular cAMP and cellular proliferation. In contrast, MC1R(wt) fibroblasts react with a decrease of intracellular cAMP and proliferation. In MC1R polymorphic fibroblasts (R163Q, R151C and V60L) both effects are significantly alleviated. Similar, but inverse effects could be found in MC1R polymorphic melanocytes (R142H and V92M) with a significantly lower cAMP increase and proliferation rate compared to MC1R(wt) melanocytes.Our results indicate that the MC1R displays reciprocal growth responses in melanocytes and fibroblasts, depending on the MC1R genotype. Thus, the MC1R seems to be not solely important for the skin pigmentary system, but also for the fibroblast function, and might influence different processes of the dermal compartment like wound healing, fibrosis and keloid formation.
Full-text · Article · Oct 2011 · Dermato-Endocrinology