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Darryl L Quarles - One of the best experts on this subject based on the ideXlab platform.
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explaining divergent observations regarding osteocalcin GPRC6A endocrine signaling
Endocrinology, 2021Co-Authors: Satoru Kenneth Nishimoto, Darryl L QuarlesAbstract:A new schema proposes that the bone-derived osteocalcin (Ocn) peptide hormone activates the G-protein-coupled receptor GPRC6A to directly regulate glucose and fat metabolism in liver, muscle, and fat, and to stimulate the release of metabolism-regulating hormones, including insulin, fibroblast growth factor 21, glucagon-like peptide 1, testosterone, and interleukin 6. Ocn/GPRC6A activation has also been implicated in cancer progression. GPRC6A is activated by cations, amino acids, and testosterone. The multiligand specificity, the regulation of energy metabolism in diverse tissues, and the coordinated release of metabolically active hormones make the GPRC6A endocrine networks unique. Recently, the significance of Ocn/GPRCA has been questioned. There is a lack of metabolic abnormalities in newly created genetically engineered Ocn- and GPRC6A-deficient mouse models. There are also paradoxical observations that GPRC6A may function as a tumor suppressor. In addition, discordant published studies have cast doubt on the function of the most prevalent uniquely human GPRC6A-KGKY polymorphism. Explanations for these divergent findings are elusive. We provide evidence that the metabolic susceptibility of genetically engineered Ocn- and GPRC6A-deficient mice is influenced by environmental challenges and genetic differences in mouse strains. In addition, the GPRC6A-KGKY polymorphism appears to be a gain-of-function variant. Finally, alternatively spliced isoforms of GPRC6A may alter ligand specificity and signaling that modulate oncogenic effects. Thus, genetic, post-translational and environmental factors likely account for the variable results regarding the functions of GPRC6A in animal models. Pending additional information, GPRC6A should remain a potential therapeutic target for regulating energy and fat metabolism, hormone production, and cancer progression.
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humanized GPRC6A kgky is a gain of function polymorphism in mice
Scientific Reports, 2020Co-Authors: Satoru K Nishimoto, Robert W. Williams, Robert A Kesterson, Darryl L QuarlesAbstract:GPRC6A is proposed to regulate energy metabolism in mice, but in humans a KGKY polymorphism in the third intracellular loop (ICL3) is proposed to result in intracellular retention and loss-of-function. To test physiological importance of this human polymorphism in vivo, we performed targeted genomic humanization of mice by using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9) system to replace the RKLP sequence in the ICL3 of the GPRC6A mouse gene with the uniquely human KGKY sequence to create GPRC6A-KGKY-knockin mice. Knock-in of a human KGKY sequence resulted in a reduction in basal blood glucose levels and increased circulating serum insulin and FGF-21 concentrations. GPRC6A-KGKY-knockin mice demonstrated improved glucose tolerance, despite impaired insulin sensitivity and enhanced pyruvate-mediated gluconeogenesis. Liver transcriptome analysis of GPRC6A-KGKY-knockin mice identified alterations in glucose, glycogen and fat metabolism pathways. Thus, the uniquely human GPRC6A-KGKY variant appears to be a gain-of-function polymorphism that positively regulates energy metabolism in mice.
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role of GPRC6A in regulating hepatic energy metabolism
Social Science Research Network, 2019Co-Authors: Satoru K Nishimoto, Robert W. Williams, Robert A Kesterson, Darryl L QuarlesAbstract:We show that GPRC6A, an osteocalcin-sensing G-protein coupled receptor GPRC6A, uniquely regulates glucose and fatty acid metabolism in the liver. Conditional deletion of GPRC6A in hepatocytes results in hepatic fat accumulation and glycogen depletion associated with impaired glucose and pyruvate tolerance and suppression of FGF-21 in mice. Conversely, knock-in of a human KGKY gain-of-function polymorphism in the 3rd intracellular loop of GPRC6A, in mice results in reduced blood glucose associated with improved glucose, insulin and pyruvate tolerance and increased FGF-21. Hepatic transcriptome analysis shows that GPRC6A has counter regulatory effects on fatty acid oxidation and synthesis and glycolysis and gluconeogenesis, and concordant effects on glycogenesis and glycogenolysis. Taken together, our studies suggest that the level of GPRC6A activation determines how glucose and FAs are utilized by the liver. GPRC6A may be a new therapeutic target for treating metabolic syndrome and its complications.
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human GPRC6A mediates testosterone induced mitogen activated protein kinases and mtorc1 signaling in prostate cancer cells
Molecular Pharmacology, 2019Co-Authors: Mohammed M Nooh, Suleiman W Bahout, Darryl L QuarlesAbstract:G protein-coupled receptor family C group 6 member A (GPRC6A) is activated by testosterone and modulates prostate cancer progression. Most humans have a GPRC6A variant that contains a recently evolved KGKY insertion/deletion in the third intracellular loop (ICL3) (designated as GPRC6AICL3_KGKY) that replaces the ancestral KGRKLP sequence (GPRC6AICL3_RKLP) present in all other species. In vitro assays purport that human GPRC6AICL3_KGKY is retained intracellularly and lacks function. These findings contrast with ligand-dependent activation and coupling to mammalian target of rapamycin complex 1 (mTORC1) signaling of endogenous human GPRC6AICL3_KGKY in PC-3 cells. To understand these discrepant results, we expressed mouse (mGPRC6AICL3_KGRKLP), human (hGPRC6AICL3_KGKY), and humanized mouse (mGPRC6AICL3_KGKY) GPRC6A into human embryonic kidney 293 cells. Our results demonstrate that mGPRC6AICL3_KGRKLP acts as a classic G protein-coupled receptor, which is expressed at the cell membrane and internalizes in response to ligand activation by testosterone. In contrast, hGPRC6AICL3_KGKY and humanized mouse mGPRC6AICL3_KGKY are retained intracellularly in ligand naive cells, yet exhibit β-arrestin-dependent signaling responses, mitogen-activated protein kinase [i.e., extracellular signal-regulated kinase (ERK)], and p70S6 kinase phosphorylation in response to testosterone, indicating that hGPRC6AICL3_KGKY is functional. Indeed, testosterone stimulates time- and dose-dependent activation of ERK, protein kinase B, and mTORC1 signaling in wild-type PC-3 cells that express endogenous GPRC6AICL3_KGKY In addition, testosterone stimulates GPRC6A-dependent cell proliferation in wild-type PC-3 cells and inhibits autophagy by activating mTORC1 effectors eukaryotic translation initiation factor 4E binding protein 1 and Unc-51 like autophagy activating kinase 1. Testosterone activation of GPRC6A has the obligate requirement for calcium in the incubation media. In contrast, in GPRC6A-deficient cells, the effect of testosterone to activate downstream signaling is abolished, indicating that human GPRC6A is required for mediating the effects of testosterone on cell proliferation and autophagy.
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computationally identified novel agonists for GPRC6A
PLOS ONE, 2018Co-Authors: Karan Kapoor, Jeremy C Smith, Jerome Baudry, Dong Jin Hwang, Duane D Miller, Darryl L QuarlesAbstract:New insights into G protein coupled receptor regulation of glucose metabolism by β-cells, skeletal muscle and liver hepatocytes identify GPRC6A as a potential therapeutic target for treating type 2 diabetes mellitus (T2D). Activating GPRC6A with a small molecule drug represents a potential paradigm-shifting opportunity to make significant strides in regulating glucose homeostasis by simultaneously correcting multiple metabolic derangements that underlie T2D, including abnormalities in β-cell proliferation and insulin secretion and peripheral insulin resistance. Using a computational, structure-based high-throughput screening approach, we identified novel tri-phenyl compounds predicted to bind to the venus fly trap (VFT) and 7-transmembrane (7-TM) domains of GPRC6A. Experimental testing found that these compounds dose-dependently stimulated GPRC6A signaling in a heterologous cell expression system. Additional chemical modifications and functional analysis identified one tri-phenyl lead compound, DJ-V-159 that demonstrated the greatest potency in stimulating insulin secretion in β-cells and lowering serum glucose in wild-type mice. Collectively, these studies show that GPRC6A is a "druggable" target for developing chemical probes to treat T2DM.
Hans Braunerosborne - One of the best experts on this subject based on the ideXlab platform.
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pharmacology and physiological function of the orphan GPRC6A receptor
Basic & Clinical Pharmacology & Toxicology, 2020Co-Authors: Christinna V Jorgensen, Hans BraunerosborneAbstract:The G protein-coupled receptor GPRC6A (GPCR, Class C, group 6, subtype A) is a Gq/11 -coupled receptor widely expressed in human and rodent tissues. The proposed endogenous ligands are L-amino acids, divalent cations, osteocalcin and testosterone. This MiniReview provides an updated overview of the literature including the latest in vitro and in vivo studies. GPRC6A forms homodimers, it undergoes constitutive internalization, and very interestingly, the reason for the intracellular retention of the human receptor has been revealed. Multiple physiological functions of GPRC6A have been suggested based on studies using three different global GPRC6A knockout (KO) mouse models where exon II, exon VI or the full locus has been deleted. The newest studies on the full locus GPRC6A KO model show intact glucose and bone homoeostasis with a minor reduction in serum osteocalcin levels. Unfortunately, the physiological function of the receptor remains elusive due to a general lack of consensus/validation of reported phenotypes of the different KO models, and more research is thus warranted to uncover the physiological function. Recent discoveries of human genetic variants that cause either a premature stop codon or an intracellular retention of the receptor point towards human population studies as the preferred approach to continue studies on the function of GPRC6A.
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metabolic and skeletal homeostasis are maintained in full locus GPRC6A knockout mice
Scientific Reports, 2019Co-Authors: Christinna V Jorgensen, Markus J Seibel, Sylvia J Gasparini, Hong Zhou, Hans BraunerosborneAbstract:The G protein-coupled receptor class C, group 6, subtype A (GPRC6A) is suggested to have a physiological function in glucose and bone metabolism, although the precise role lacks consensus due to varying findings in different knockout (KO) mouse models and inconsistent findings on the role of osteocalcin, a proposed GPRC6A agonist. We have further characterized a full locus GPRC6A KO model with respect to energy metabolism, including a long-term high-dose glucocorticoid metabolic challenge. Additionally, we analyzed the microarchitecture of tibiae from young, middle-aged and aged GPRC6A KO mice and wildtype (WT) littermates. Compared to WT, vehicle-treated KO mice presented with normal body composition, unaltered insulin sensitivity and basal serum insulin and glucose levels. Corticosterone (CS) treatment resulted in insulin resistance, abnormal fat accrual, loss of lean mass and suppression of serum osteocalcin levels in both genotypes. Interestingly, serum osteocalcin and skeletal osteocalcin mRNA levels were significantly lower in vehicle-treated GPRC6A KO mice compared to WT animals. However, WT and KO age groups did not differ in long bone mass and structure assessed by micro-computed tomography. We conclude that GPRC6A is not involved in glucose metabolism under normal physiological conditions, nor does it mediate glucocorticoid-induced dysmetabolism in mice. Moreover, GPRC6A does not appear to possess a direct, non-compensable role in long bone microarchitecture under standard conditions.
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the GPRC6A receptor displays constitutive internalization and sorting to the slow recycling pathway
Journal of Biological Chemistry, 2017Co-Authors: Stine Engesgaard Jacobsen, Ina Ammendrupjohnsen, Anna M Jansen, Ulrik Gether, Kenneth L Madsen, Hans BraunerosborneAbstract:The class C G protein-coupled receptor GPRC6A is a putative nutrient-sensing receptor and represents a possible new drug target in metabolic disorders. However, the specific physiological role of this receptor has yet to be identified, and the mechanisms regulating its activity and cell surface availability also remain enigmatic. In the present study, we investigated the trafficking properties of GPRC6A by use of both a classical antibody feeding internalization assay in which cells were visualized using confocal microscopy and a novel internalization assay that is based on real-time measurements of fluorescence resonance energy transfer. Both assays revealed that GPRC6A predominantly undergoes constitutive internalization, whereas the agonist-induced effects were imperceptible. Moreover, postendocytic sorting was investigated by assessing the co-localization of internalized GPRC6A with selected Rab protein markers. Internalized GPRC6A was mainly co-localized with the early endosome marker Rab5 and the long loop recycling endosome marker Rab11 and to a much lesser extent with the late endosome marker Rab7. This suggests that upon agonist-independent internalization, GPRC6A is recycled via the Rab11-positive slow recycling pathway, which may be responsible for ensuring a persistent pool of GPRC6A receptors at the cell surface despite chronic agonist exposure. Distinct trafficking pathways have been reported for several of the class C receptors, and our results thus substantiate that non-canonical trafficking mechanisms are a common feature for the nutrient-sensing class C family that ensure functional receptors in the cell membrane despite prolonged agonist exposure.
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robust glp 1 secretion by basic l amino acids does not require the GPRC6A receptor
Diabetes Obesity and Metabolism, 2017Co-Authors: Christoffer Clemmensen, Christinna V Jorgensen, Sanela Smajilovic, Hans BraunerosborneAbstract:The G protein-coupled receptor GPRC6A (GPCR, Class C, group 6, subtype A) has been proposed to be a sensor for basic L-amino acids that are hypothesized to translate ingestive behaviour to endocrine information. However, the contribution of the GPRC6A receptor to L-amino acid-induced glucagon-like peptide 1 (GLP-1) secretion is unclear. Therefore, to discover whether the GPRC6A receptor is indispensible for amino acid-induced secretion of GLP-1, we treated, with oral gavage, GPRC6A knock-out (KO) and wild-type (WT) littermate mice with GPRC6A ligands (L-arginine and L-ornithine) and assessed GLP-1 levels in circulation. We found that oral administration of both L-arginine and L-ornithine significantly increased total plasma GLP-1 levels to a similar level in GPRC6A KO and WT mice 15 minutes after gavage (both amino acids) and accumulated up to 60 minutes after gavage (L-arginine). Conversely, GLP-1 secretion at the 30- and 60-minute time points in the KO mice was attenuated and did not reach statistical significance. In summary, these data confirm that L-arginine is a potent GLP-1 secretagogue and show that the main effect occurs independently of GPRC6A. In addition, this is the first study to show that also L-ornithine powerfully elicits GLP-1 release in vivo.
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selective allosteric antagonists for the g protein coupled receptor GPRC6A based on the 2 phenylindole privileged structure scaffold
Journal of Medicinal Chemistry, 2015Co-Authors: Henrik Johansson, Hans Braunerosborne, David E Gloriam, Michael W Boesgaard, Lenea Norskovlauritsen, Inna Larsen, Sebastiaan Kuhne, Daniel Sejer PedersenAbstract:G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1-3). Herein, we present the first structure-activity relationship study for the 2-arylindole antagonist 3, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making 7 and 34b the most potent and selective antagonists for the GPRC6A receptor reported to date.
Mostafa A Elsayed - One of the best experts on this subject based on the ideXlab platform.
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antiandrogen gold nanoparticles dual target and overcome treatment resistance in hormone insensitive prostate cancer cells
Bioconjugate Chemistry, 2012Co-Authors: Erik C Dreaden, Berkley E Gryder, Adegboyega K Oyelere, Lauren A Austin, Brice Tene A Defo, Steven C Hayden, Min Pi, Darryl L Quarles, Mostafa A ElsayedAbstract:Prostate cancer is the most commonly diagnosed cancer among men in the developed countries.(1) One in six males in the U.S.(2) and one in nine males in the U.K.(3) will develop the disease at some point during their lifetime. Despite advances in prostate cancer screening, more than a quarter of a million men die from the disease every year(1) due primarily to treatment-resistance and metastasis. Colloidal nanotechnologies can provide tremendous enhancements to existing targeting/treatment strategies for prostate cancer to which malignant cells are less sensitive. Here, we show that antiandrogen gold nanoparticles—multivalent analogues of antiandrogens currently used in clinical therapy for prostate cancer—selectively engage two distinct receptors, androgen receptor (AR), a target for the treatment of prostate cancer, as well as a novel G-protein coupled receptor, GPRC6A, that is also upregulated in prostate cancer. These nanoparticles selectively accumulated in hormone-insensitive and chemotherapy-resista...
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antiandrogen gold nanoparticles dual target and overcome treatment resistance in hormone insensitive prostate cancer cells
Bioconjugate Chemistry, 2012Co-Authors: Erik C Dreaden, Berkley E Gryder, Adegboyega K Oyelere, Lauren A Austin, Brice Tene A Defo, Steven C Hayden, Darryl L Quarles, Mostafa A ElsayedAbstract:Prostate cancer is the most commonly diagnosed cancer among men in the developed countries.(1) One in six males in the U.S.(2) and one in nine males in the U.K.(3) will develop the disease at some point during their lifetime. Despite advances in prostate cancer screening, more than a quarter of a million men die from the disease every year(1) due primarily to treatment-resistance and metastasis. Colloidal nanotechnologies can provide tremendous enhancements to existing targeting/treatment strategies for prostate cancer to which malignant cells are less sensitive. Here, we show that antiandrogen gold nanoparticles--multivalent analogues of antiandrogens currently used in clinical therapy for prostate cancer--selectively engage two distinct receptors, androgen receptor (AR), a target for the treatment of prostate cancer, as well as a novel G-protein coupled receptor, GPRC6A, that is also upregulated in prostate cancer. These nanoparticles selectively accumulated in hormone-insensitive and chemotherapy-resistant prostate cancer cells, bound androgen receptor with multivalent affinity, and exhibited greatly enhanced drug potency versus monovalent antiandrogens currently in clinical use. Further, antiandrogen gold nanoparticles selectively stimulated GPRC6A with multivalent affinity, demonstrating that the delivery of nanoscale antiandrogens can also be facilitated by the transmembrane receptor in order to realize increasingly selective, increasingly potent therapy for treatment-resistant prostate cancers.
Reuben Lotan - One of the best experts on this subject based on the ideXlab platform.
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gprc5a deletion enhances the transformed phenotype in normal and malignant lung epithelial cells by eliciting persistent stat3 signaling induced by autocrine leukemia inhibitory factor
Cancer Research, 2010Co-Authors: Yulong Chen, Jiong Deng, Junya Fujimoto, Tao Yan Men, Humam Kadara, Dafna Lotan, Reuben LotanAbstract:Signal transducers and activators of transcription 3 (Stat3) is activated by cytokines and growth factors in lung cancers and regulates expression of genes implicated in cell growth, survival, and transformation. Previously, we found that mice with a deletion of the G protein-coupled receptor, family C, group 5, member a (Gprc5a) gene develop lung tumors, indicating that Gprc5a is a tumor suppressor. Herein, we show that epithelial cells from Gprc5a knockout mouse lung (Gprc5a(-/-) cells) survive better in vitro in medium deprived of exogenous growth factors and form more colonies in semisolid medium than their counterparts from wild-type mice (Gprc5a(+/+) cells). Stat3 tyrosine 705 phosphorylation and expression of several Stat3-regulated antiapoptotic genes were higher in Gprc5a(-/-) than in Gprc5a(+/+) cells. Both cell types secreted leukemia inhibitory factor (Lif); however, whereas Stat3 activation was persistent in Gprc5a(-/-) cells, it was transient in Gprc5a(+/+) cells. Lung adenocarcinoma cells isolated from Gprc5a(-/-) mice also exhibited autocrine Lif-mediated Stat3 activation. The level of Socs3, the endogenous Stat3 inhibitory protein, was higher in Gprc5a(+/+) than in Gprc5a(-/-) cells, and expression of the tumor suppressor stabilized Socs3. Inhibition of Stat3 signaling in Gprc5a(-/-) normal and cancer cells by the Janus-activated kinase 2 inhibitor AG490 or by a dominant negative Stat3(Y705F) increased starvation-induced apoptosis and inhibited colony formation. These results show that persistent Stat3 activation is important for the survival and transformation of Gprc5a(-/-) lung cells and suggest that the tumor suppressive effects of Gprc5a are mediated, at least in part, by inhibition of Stat3 signaling through Socs3 stabilization.
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comparative functional genomics analysis of nnk tobacco carcinogen induced lung adenocarcinoma development in gprc5a knockout mice
PLOS ONE, 2010Co-Authors: Junya Fujimoto, Tao Yan Men, Carolyn S Van Pelt, Humam Kadara, Dafna Lotan, Reuben LotanAbstract:Background Improved understanding of lung cancer development and progression, including insights from studies of animal models, are needed to combat this fatal disease. Previously, we found that mice with a knockout (KO) of G-protein coupled receptor 5A (Gprc5a) develop lung tumors after a long latent period (12 to 24 months). Methodology/Principal Findings To determine whether a tobacco carcinogen will enhance tumorigenesis in this model, we administered 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) i.p. to 2-months old Gprc5a-KO mice and sacrificed groups (n = 5) of mice at 6, 9, 12, and 18 months later. Compared to control Gprc5a-KO mice, NNK-treated mice developed lung tumors at least 6 months earlier, exhibited 2- to 4-fold increased tumor incidence and multiplicity, and showed a dramatic increase in lesion size. A gene expression signature, NNK-ADC, of differentially expressed genes derived by transcriptome analysis of epithelial cell lines from normal lungs of Gprc5a-KO mice and from NNK-induced adenocarcinoma was highly similar to differential expression patterns observed between normal and tumorigenic human lung cells. The NNK-ADC expression signature also separated both mouse and human adenocarcinomas from adjacent normal lung tissues based on publicly available microarray datasets. A key feature of the signature, up-regulation of Ube2c, Mcm2, and Fen1, was validated in mouse normal lung and adenocarcinoma tissues and cells by immunohistochemistry and western blotting, respectively. Conclusions/Significance Our findings demonstrate that lung tumorigenesis in the Gprc5a-KO mouse model is augmented by NNK and that gene expression changes induced by tobacco carcinogen(s) may be conserved between mouse and human lung epithelial cells. Further experimentation to prove the reliability of the Gprc5a knockout mouse model for the study of tobacco-induced lung carcinogenesis is warranted.
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knockout of the tumor suppressor gene gprc5a in mice leads to nf κb activation in airway epithelium and promotes lung inflammation and tumorigenesis
Cancer Prevention Research, 2010Co-Authors: Jiong Deng, Junya Fujimoto, Tao Yan Men, Carolyn S Van Pelt, Yulong Chen, Xiao Feng Lin, Humam Kadara, Qingguo Tao, Dafna Lotan, Reuben LotanAbstract:Mouse models can be useful for increasing the understanding of lung tumorigenesis and assessing the potential of chemopreventive agents. We explored the role of inflammation in lung tumor development in mice with knockout of the tumor suppressor Gprc5a. Examination of normal lung tissue and tumors from 51 Gprc5a(+/+) (adenoma incidence, 9.8%; adenocarcinoma, 0%) and 38 Gprc5a(-/-) mice (adenoma, 63%; adenocarcinoma, 21%) revealed macrophage infiltration into lungs of 45% of the Gprc5a(-/-) mice and 8% of Gprc5a(+/+) mice and the direct association of macrophages with 42% of adenomas and 88% of adenocarcinomas in the knockout mice. Gprc5a(-/-) mouse lungs contained higher constitutive levels of proinflammatory cytokines and chemokines and were more sensitive than lungs of Gprc5a(+/+) mice to stimulation of NF-kappaB activation by lipopolysaccharide in vivo. Studies with epithelial cells cultured from tracheas of Gprc5a(-/-) and Gprc5a(+/+) mice revealed that Gprc5a loss is associated with increased cell proliferation, resistance to cell death in suspension, and increased basal, tumor necrosis factor alpha-induced, and lipopolysaccharide-induced NF-kappaB activation, which were reversed partially in Gprc5a(-/-) adenocarcinoma cells by reexpression of Gprc5a. Compared with Gprc5a(+/+) cells, the Gprc5a(-/-) cells produced higher levels of chemokines and cytokines and their conditioned medium induced more extensive macrophage migration. Silencing Gprc5a and the p65 subunit of NF-kappaB in Gprc5a(+/+) and Gprc5a(-/-) cells, respectively, reversed these effects. Thus, Gprc5a loss enhances NF-kappaB activation in lung epithelial cells, leading to increased autocrine and paracrine interactions, cell autonomy, and enhanced inflammation, which may synergize in the creation of a tumor-promoting microenvironment.
Yashiro Masakazu - One of the best experts on this subject based on the ideXlab platform.
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Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer
'EMBO', 2020Co-Authors: Moyano-galceran Lidia, Pietila, Elina A., Turunen S. Pauliina, Corvigno Sara, Hjerpe Elisabet, Bulanova Daria, Joneborg Ulrika, Alkasalias Twana, Miki Yuichiro, Yashiro MasakazuAbstract:Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non-genetic resistance mechanisms was long neglected. Using high-grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy-induced ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2-S897 phosphorylation and EphA2-GPRC5A co-regulation, thereby facilitating a signaling shift to the canonical tumor-suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum-resistant EphA2(high), GPRC5A(high) cells to the therapy-induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo-resistant cells to RSK1/2-EphA2-pS897 pathway inhibition
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Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer
'EMBO', 2020Co-Authors: Moyano-galceran Lidia, Pietila, Elina A., Turunen S. Pauliina, Corvigno Sara, Hjerpe Elisabet, Bulanova Daria, Joneborg Ulrika, Alkasalias Twana, Miki Yuichiro, Yashiro MasakazuAbstract:Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non-genetic resistance mechanisms was long neglected. Using high-grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy-induced ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2-S897 phosphorylation and EphA2-GPRC5A co-regulation, thereby facilitating a signaling shift to the canonical tumor-suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum-resistant EphA2(high), GPRC5A(high) cells to the therapy-induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo-resistant cells to RSK1/2-EphA2-pS897 pathway inhibition.Peer reviewe
