Magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway

Lee, Cheol-Jung; Lee, Mee-Hyun; Yoo, Sun-Mi; Choi, Kyung-Il; Song, Ji-Hong; Jang, Ja Young; Oh, Sei‐Ryang; Ryu, Hyung Won; Lee, Hye-Suk; Surh, Young‐Joon; Cho, Yong‐Yeon

doi:10.1186/s12885-015-1580-7

Cited by 52 publications

(40 citation statements)

References 47 publications

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“…To examine whether magnolin‐induced senescence is the cellular senescence or senescence‐associated secretory phenotype (SASP), we firstly examine the transactivation activity of NF‐κB, which is an important transcription factor inducing gene expression of SASP related genes . Our results demonstrated that magnolin suppressed NF‐κB transactivation activity (Figure C) as similar as our previous report . In contrast, the inhibition of NF‐κB transactivation activity was not observed in SKOV3 cells (Figure C).…”

Section: Resultssupporting

confidence: 86%

“…21 Our results demonstrated that magnolin suppressed NF-κB transactivation activity ( Figure 4C) as similar as our previous report. 22 In contrast, the inhibition of NF-κB transactivation activity was not observed in SKOV3 cells ( Figure 4C). Moreover, magnolin did not induce or not alter the expression of IL-6, IL-8, IL-1β, MMP-1, and MMP-3 ( Figure 4D), which are well known the representative SASP markers.…”

Section: D Ovarian Cancer Cells Inhibits Cell Proliferation By Enhmentioning

confidence: 87%

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Magnolin targeting of ERK1/2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells

Song

Lee

et al. 2018

Molecular Carcinogenesis

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Ras/Raf/MEKs/ERKs and PI3 K/Akt/mTOR signaling pathways have key roles in cancer development and growth processes, as well as in cancer malignance and chemoresistance. In this study, we screened the therapeutic potential of magnolin using 15 human cancer cell lines and combined magnolin sensitivity with the CCLE mutaome analysis for relevant mutation information. The results showed that magnolin efficacy on cell proliferation inhibition were lower in TOV-112D ovarian cancer cells than that in SKOV3 cells by G1 and G2/M cell cycle phase accumulation. Notably, magnolin suppressed colony growth of TOV-112D cells in soft agar, whereas colony growth of SKOV3 cells in soft agar was not affected by magnolin treatment. Interestingly, phospho-protein profiles in the MAPK and PI3 K signaling pathways indicated that SKOV3 cells showed marked increase of Akt phosphorylation at Thr308 and Ser473 and very weak ERK1/2 phosphorylation levels by EGF stimulation. The phospho-protein profiles in TOV-112D cells were the opposite of those of SKOV3 cells. Importantly, magnolin treatment suppressed phosphorylation of RSKs in TOV-112D, but not in SKOV3 cells. Moreover, magnolin increased SA-β-galactosidase-positive cells in a dose-dependent manner in TOV-112D cells, but not in SKOV3 cells. Notably, oral administration of Shin-Yi fraction 1, which contained magnolin approximately 53%, suppressed TOV-112D cell growth in athymic nude mice by induction of p16 and p27 . Taken together, targeting of ERK1 and ERK2 is suitable for the treatment of ovarian cancer cells that do not harbor the constitutive active P13 K mutation and the loss-of-function mutations of the p16 and/or p53 tumor suppressor proteins.

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Section: Resultssupporting

confidence: 86%

Section: D Ovarian Cancer Cells Inhibits Cell Proliferation By Enhmentioning

confidence: 87%

Magnolin targeting of ERK1/2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells

Song

Lee

et al. 2018

Molecular Carcinogenesis

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“…A key signaling node induced and activated by the Her2/Mapk/Erk pathway is Rsk2 (17,18), which, in turn, promotes numerous down-stream signaling pathways associated with the development of EMT and metastasis including integrin activation, the expression of matrix metalloproteinases, the expression/activation of Creb, Stat3, cSrc, Fak, Pax, and actin polymerization (13,14,39–43). Activation of these same signaling pathways is also seen in breast tumors from patients that have developed resistance to chemotherapy (24,25).…”

Section: Discussionmentioning

confidence: 99%

“…A potential role in cell migration was first proposed when Rsk2 was found to phosphorylate the cytoskeleton-associated protein filamin A (16). Recently, Rsk2 was identified as an effector of Ras/Erk-mediated EMT and its knockdown reduces metastasis in animal models (17,18). A genome-wide mRNA analysis revealed that Erk/Rsk signaling affects the expression of over 50 genes from diverse pathways responsible for cell motility and invasiveness (19).…”

Section: Introductionmentioning

confidence: 99%

Melatonin Represses Metastasis inHer2-Postive Human Breast Cancer Cells by Suppressing RSK2 Expression

Mao

Summers

Xiang

et al. 2016

Molecular Cancer Research

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The importance of the circadian/melatonin signal in suppressing the metastatic progression of breast and other cancers has been reported by numerous laboratories including our own. Currently, the mechanisms underlying the anti-metastatic actions of melatonin have not been well established. In the present study, the anti-metastatic actions of melatonin were evaluated and compared on the ERα-negative, Her2-positive SKBR-3 breast tumor cell line and ERα-positive MCF-7 cells overexpressing a constitutively active HER2.1 construct (MCF-7Her2.1 cells). Activation of Her2 is reported to induce the expression and/or phosphorylation-dependent activation of numerous kinases and transcription factors that drive drug resistance and metastasis in breast cancer. A key signaling node activated by the Her2/Mapk/Erk pathway is Rsk2, which has been shown to induce numerous signaling pathways associated with the development of epithelial-to-mesenchymal transition (EMT) and metastasis including: Creb, Stat3, cSrc, Fak, Pax, Fascin, and actin polymerization. The data demonstrate that melatonin (both endogenous and exogenous) significantly represses this invasive/metastatic phenotype through a mechanism that involves the suppression of EMT, either by promoting mesenchymal-to-epithelial transition (MET), and/or by inhibiting key signaling pathways involved in later stages of metastasis. These data, combined with our earlier in vitro studies, support the concept that maintenance of elevated and extended duration of nocturnal melatonin levels plays a critical role in repressing the metastatic progression of breast cancer.

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“…5A) and JB6 cells (Fig. 5D) [Cho et al, 2012;Keum et al, 2013;Yao et al, 2014;Lee et al, 2015]. However, the substrates of RSK2 which are related with COX-2 expression and histone H3 ser10 and IkBa ser32 phosphorylation are inhibited by osajin in HaCaT (Fig.…”

Section: Osajin Inhibits the Downstream Of Rsk2 Pathwaymentioning

confidence: 91%

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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Magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway

Cited by 52 publications

References 47 publications

Magnolin targeting of ERK1/2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells

Magnolin targeting of ERK1/2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells

Melatonin Represses Metastasis inHer2-Postive Human Breast Cancer Cells by Suppressing RSK2 Expression

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

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