Kaempferol Targets RSK2 and MSK1 to Suppress UV Radiation-Induced Skin Cancer

Yao, Ke; Chen, Hanyong; Liu, Kangdong; Langfald, Alyssa; Yang, Ge; Zhang, Yi; Yu, Dong Hoon; Kim, Myoung Ok; Lee, Mee-Hyun; Li, Haitao; Bae, Ki Beom; Kim, Hong-Gyum; Ma, Weiya; Bode, Ann M.; Dong, Ziming; Dong, Zigang

doi:10.1158/1940-6207.capr-14-0126

Cited by 58 publications

(42 citation statements)

References 48 publications

(55 reference statements)

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“…Notably, EGCG inhibited colony formation by 15% at 10 μM (Fig 5Ac) but dramatically inhibited colony formation by 85% at 20 μM (Fig 5Ad-f). Kaempferol, an RSK2 NTD inhibitor, was used as a positive control (Fig 5Ag-h) [28, 32]. Similar results were also observed for the effect of EGCG or kaempferol on colony size (S2 Fig).…”

Section: Resultssupporting

confidence: 63%

Computational and Biochemical Discovery of RSK2 as a Novel Target for Epigallocatechin Gallate (EGCG)

et al. 2015

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The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG). Protein interaction with EGCG is a critical step for mediating the effects of EGCG on the regulation of various key molecules involved in signal transduction. By using computational docking screening methods for protein identification, we identified a serine/threonine kinase, 90-kDa ribosomal S6 kinase (RSK2), as a novel molecular target of EGCG. RSK2 includes two kinase catalytic domains in the N-terminal (NTD) and the C-terminal (CTD) and RSK2 full activation requires phosphorylation of both terminals. The computer prediction was confirmed by an in vitro kinase assay in which EGCG inhibited RSK2 activity in a dose-dependent manner. Pull-down assay results showed that EGCG could bind with RSK2 at both kinase catalytic domains in vitro and ex vivo. Furthermore, results of an ATP competition assay and a computer-docking model showed that EGCG binds with RSK2 in an ATP-dependent manner. In RSK2+/+ and RSK2-/- murine embryonic fibroblasts, EGCG decreased viability only in the presence of RSK2. EGCG also suppressed epidermal growth factor-induced neoplastic cell transformation by inhibiting phosphorylation of histone H3 at Ser10. Overall, these results indicate that RSK2 is a novel molecular target of EGCG.

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Section: Resultssupporting

confidence: 63%

Computational and Biochemical Discovery of RSK2 as a Novel Target for Epigallocatechin Gallate (EGCG)

et al. 2015

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“…After screening 68 kinases related to inflammation, we found that osajin inhibits RSK2 in an ATPcompetitive manner. Previous studies show that RSK2 is targeted by kaempferol and epigallocatechin gallate which have similar structure with osajin [Yao et al, 2014;Chen et al, 2015]. Based on Fig.…”

Section: Discussionmentioning

confidence: 92%

“…It is activated by cellular stresses such as sUV [Cho et al, 2012]. Previous studies show that RSK2 is targeted by kaempferol and epigallocatechin gallate which have similar structure with osajin [Yao et al, 2014;Chen et al, 2015]. Previous studies show that RSK2 is targeted by kaempferol and epigallocatechin gallate which have similar structure with osajin [Yao et al, 2014;Chen et al, 2015].…”

Section: Discussionmentioning

confidence: 99%

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Osajin Inhibits Solar UV‐Induced Cyclooxygenase‐2 Expression Through Direct Inhibition of RSK2

Kim

Heo

Lee

2017

J of Cellular Biochemistry

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Solar ultraviolet light (sUV) has been shown to promote the development of skin disorders including inflammation, photoaging, and skin carcinogenesis. Osajin is the major bioactive isoflavone present in the fruit of Maclura pomifera, commonly referred to as the Osage orange. In this study, we observed that osajin inhibited sUV-induced cyclooxygenase (COX)-2 protein expression in both HaCaT and JB6 cells. COX-2 is a major mediator of skin inflammation. sUV activated the transcription factors nuclear factor-κB and activator protein-1 which, in turn, induces COX-2 expression. Osajin inhibited transactivation of these transcription factors. We identified RSK2 as an inhibitory target of osajin by screening against 68 kinases related to inflammation. Osajin binds with RSK2 directly in an ATP-competitive manner. Computer modeling simulated a plausible binding orientation between osajin and RSK2. Osajin inhibited sUV-induced phosphorylation of histone H3, a substrate of RSK2. However, sUV-induced phosphorylation of extracellular signal-regulated kinases, p38 kinase, c-Jun N-terminal kinase and Akt, which are signaling factors upstream of RSK2, was unchanged in the presence of osajin. The anti-inflammatory effects and molecular mechanism of osajin suggest that it may have utility as a functional food for skin health and cosmetic ingredient. J. Cell. Biochem. 118: 4080-4087, 2017. © 2017 Wiley Periodicals, Inc.

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“…While CREB activation occurs in response to pro-growth and pro-survival stimuli, it is also phosphorylated in response to harmful or stress stimuli, such as UV irradiation and hypoxia [42], due to an upregulation of the mitogen- and stress-activated protein kinase-1 [43]. Indeed, an increased activity of total and phosphorylated CREB along with a decreased localization of pCREB in the nucleus was demonstrated under hypoxia in parental HER-2/neu + cells.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-mediated alterations and their role in the HER-2/neuregulated CREB status and localization

et al. 2016

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The cAMP-responsive element-binding protein (CREB) is involved in the tumorigenicity of HER-2/neu-overexpressing murine and human tumor cells, but a link between the HER-2/neu-mediated CREB activation, its posttranslational modification and localization and changes in the cellular metabolism, due to an altered (tumor) microenvironment remains to be established. The present study demonstrated that shRNA-mediated silencing of CREB in HER-2/neu-transformed cells resulted in decreased tumor formation, which was associated with reduced angiogenesis, but increased necrotic and hypoxic areas in the tumor. Hypoxia induced pCREBSer133, but not pCREBSer121 expression in HER-2/neu-transformed cells. This was accompanied by upregulation of the hypoxia-inducible genes GLUT1 and VEGF, increased cell migration and matrix metalloproteinase-mediated invasion. Treatment of HER-2/neu+ cells with signal transduction inhibitors targeting in particular HER-2/neu was able to revert hypoxia-controlled CREB activation. In addition to changes in the phosphorylation, hypoxic response of HER-2/neu+ cells caused a transient ubiquitination and SUMOylation as well as a co-localization of nuclear CREB to the mitochondrial matrix. A mitochondrial localization of CREB was also demonstrated in hypoxic areas of HER-2/neu+ mammary carcinoma lesions. This was accompanied by an altered gene expression pattern, activity and metabolism of mitochondria leading to an increased respiratory rate, oxidative phosphorylation and mitochondrial membrane potential and consequently to an enhanced apoptosis and reduced cell viability. These data suggest that the HER-2/neu-mediated CREB activation caused by a hypoxic tumor microenvironment contributes to the neoplastic phenotype of HER-2/neu+ cells at various levels.

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Kaempferol Targets RSK2 and MSK1 to Suppress UV Radiation-Induced Skin Cancer

Cited by 58 publications

References 48 publications

Computational and Biochemical Discovery of RSK2 as a Novel Target for Epigallocatechin Gallate (EGCG)

Computational and Biochemical Discovery of RSK2 as a Novel Target for Epigallocatechin Gallate (EGCG)

Osajin Inhibits Solar UV‐Induced Cyclooxygenase‐2 Expression Through Direct Inhibition of RSK2

Hypoxia-mediated alterations and their role in the HER-2/neuregulated CREB status and localization

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