Novel effects of FTY720 on perinuclear reorganization of keratin network induced by sphingosylphosphorylcholine: Involvement of protein phosphatase 2A and G-protein-coupled receptor-12

Park, Mi Kyung; Park, Soyeun; Kim, Hyun Ji; Kim, Young Ho; Kim, So Yeon; Kang, Gyeoung Jin; Byun, Hyun Jung; Kim, Sang Hee; Lee, Ho; Lee, Chang Hoon

doi:10.1016/j.ejphar.2016.02.024

Cited by 17 publications

(28 citation statements)

References 46 publications

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“…GPR12: cancer Keratin 8 (K8) is involved in cancer cell migration and invasion by changing the viscoelasticity of cancer cells [55]. Park et al [56] showed that overexpression of GPR12 induces K8 phosphorylation and reorganization, and silencing of the receptor reduces both of these K8 processes. These data indicate that GPR12 may be a potential target for prevention of metastasis by developing compounds that can block GPR12.…”

Section: Gpr12: Cell Survival and Proliferationmentioning

confidence: 99%

GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol

et al. 2018

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The G protein-coupled receptors 3, 6, and 12 (GPR3, GPR6, and GPR12) comprise a family of closely related orphan receptors with no confirmed endogenous ligands. These receptors are constitutively active and capable of signaling through G protein-mediated and non-G protein-mediated mechanisms. These orphan receptors have previously been reported to play important roles in many normal physiological functions and to be involved in a variety of pathological conditions. Although they are orphans, GPR3, GPR6, and GPR12 are phylogenetically most closely related to the cannabinoid receptors. Using β-arrestin2 recruitment and cAMP accumulation assays, we recently found that the nonpsychoactive phytocannabinoid cannabidiol (CBD) is an inverse agonist for GPR3, GPR6, and GPR12. This discovery highlights these orphan receptors as potential new molecular targets for CBD, provides novel mechanisms of action, and suggests new therapeutic uses of CBD for illnesses such as Alzheimer's disease, Parkinson's disease, cancer, and infertility. Furthermore, identification of CBD as a new inverse agonist for GPR3, GPR6, and GPR12 provides the initial chemical scaffolds upon which potent and efficacious agents acting on these receptors can be developed, with the goal of developing chemical tools for studying these orphan receptors and ultimately new therapeutic agents.

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Section: Gpr12: Cell Survival and Proliferationmentioning

confidence: 99%

GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol

et al. 2018

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“…However, the reports on GPR4 and OGR1 were retracted (Retraction, 2005(Retraction, , 2006. GPR12 is known to be a high-affinity receptor for SPC and to be involved in neuronal differentiation and keratin reorganization [14,69]. Interestingly, GPR12 (SPC receptor) and CCND1 expression has significant inverse correlation with overall survival (n = 59, p = 0.006; n = 158, p = 0.018), relapse free survival (n = 100, p = 0.024; n = 158, p = 0.038), and metastasis free survival (n = 100, p = 0.037; n = 178, p = 0.026) in several microarray sets (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Novel effects of sphingosylphosphorylcholine on invasion of breast cancer: Involvement of matrix metalloproteinase-3 secretion leading to WNT activation

Kim

Kang

Kim

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Sphingosylphosphorylcholine (SPC) participates in several cellular processes including metastasis. SPC induces keratin reorganization and regulates the viscoelasticity of metastatic cancer cells including PANC-1 cancer cells leading to enhanced migration and invasion. The role of SPC and the relevant mechanism in invasion of breast cell are as yet unknown. SPC dose-dependently induces invasion of breast cancer cells or breast immortalized cells. Reverse transcription polymerase chain reaction and Western blot analyses of MCF10A and ZR-75-1 cells indicated that SPC induces expression and secretion of matrix metalloproteinase-3 (MMP3). From online KMPLOT, relapse free survival is high in patients having low MMP3 expressed basal breast cancer (n=581, p=0.032). UK370106 (MMP3 inhibitor) or gene silencing of MMP3 markedly inhibited the SPC-induced invasion of MCF10A cells. An extracellular signal-regulated kinase (ERK) inhibitor, PD98059, significantly suppressed the secretion and the gelatinolytic activity of MMP3, and invasion in MCF10A cells. Over-expression of ERK1 and ERK2 promoted both the expression and secretion of MMP3. In contrast, gene silencing of ERK1 and ERK2 attenuated the secretion of MMP3 in MCF10A cells. The effects of SPC-induced MMP3 secretion on β-catenin and TCF/lymphoid enhancer factor (LEF) promoter activity were examined since MMP3 indirectly activates canonical Wnt signaling. SPC induced translocation of β-catenin to nucleus and increased TCF/LEF promoter activity. These events were suppressed by UK370106 or PD98059. Wnt inhibitor, FH535 inhibited SPC-induced MMP3 secretion and invasion. Taken together, these results suggest that SPC induces MMP3 expression and secretion via ERK leading to Wnt activation.

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“…Our discovery that GPR12 is a novel target for CBD has important implications. For example, previously GPR12 has been suggested to be relevant to cancer metastasis [16]. Specifically, it has been shown that silencing of GPR12 led to a reduction of phosphorylation and reorganization of keratin 8 (K8) filaments, which modulate the viscoelasticity of metastatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, it has been shown that silencing of GPR12 led to a reduction of phosphorylation and reorganization of keratin 8 (K8) filaments, which modulate the viscoelasticity of metastatic cancer cells. In contrast, GPR12 overexpression stimulated K8 phosphorylation and reorganization [16]. These findings indicate that GPR12 may be a potential target for a novel class of therapeutic agents that are able to adjust viscoelasticity of cancerous cells, thus preventing tumor metastasis.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol, a novel inverse agonist for GPR12

Brown

Laun

Song

2017

Biochemical and Biophysical Research Communications

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GPR12 is a constitutively active, Gs protein-coupled receptor that currently has no confirmed endogenous ligands. GPR12 may be involved in physiological processes such as maintenance of oocyte meiotic arrest and brain development, as well as pathological conditions such as metastatic cancer. In this study, the potential effects of various classes of cannabinoids on GPR12 were tested using a cAMP accumulation assay. Our data demonstrate that cannabidiol (CBD), a major non-psychoactive phytocannabinoid, acted as an inverse agonist to inhibit cAMP accumulation stimulated by the constitutively active GPR12. Thus, GPR12 is a novel molecular target for CBD. The structure-activity relationship studies of CBD indicate that both the free hydroxyl and the pentyl side chain are crucial for the effects of CBD on GPR12. Furthermore, studies using cholera toxin, which blocks Gs protein and pertussis toxin, which blocks Gi protein, revealed that Gs, but not Gi is involved in the inverse agonism of CBD on GPR12. CBD is a promising novel therapeutic agent for cancer, and GPR12 has been shown to alter viscoelasticity of metastatic cancer cells. Since we have demonstrated that CBD is an inverse agonist for GPR12, this provides novel mechanism of action for CBD, and an initial chemical scaffold upon which highly potent and efficacious agents acting on GPR12 may be developed with the ultimate goal of blocking cancer metastasis.

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Novel effects of FTY720 on perinuclear reorganization of keratin network induced by sphingosylphosphorylcholine: Involvement of protein phosphatase 2A and G-protein-coupled receptor-12

Cited by 17 publications

References 46 publications

GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol

GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol

Novel effects of sphingosylphosphorylcholine on invasion of breast cancer: Involvement of matrix metalloproteinase-3 secretion leading to WNT activation

Cannabidiol, a novel inverse agonist for GPR12

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