Role and Regulation of STAT3 Phosphorylation at Ser727 in Melanocytes and Melanoma Cells

Sakaguchi, Masanobu; Oka, Masahiro; Iwasaki, Tetsushi; Fukami, Yasuo; Nishigori, Chikako

doi:10.1038/jid.2012.45

Cited by 89 publications

(66 citation statements)

References 33 publications

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“…A previous study showed significantly higher nuclear localization of p-Stat3-Ser727 in choriocarcinoma [28]. Another recent report has proved that Ser727 phosphorylation is associated with cell survival activity and nuclear translocation of STAT3 in melanoma cells [29]. In addition, this study demonstrated that Ser727 is frequently phosphorylated in the absence of Tyr705 phosphorylation in melanoma cells in vivo, particularly in in situ lesions of acral lentiginous melanoma (ALM) tissues.…”

Section: Discussionsupporting

confidence: 53%

Aberrantly activated pSTAT3-Ser727 in human endometrial cancer is suppressed by HO-3867, a novel STAT3 inhibitor

Tierney

McCann

Naidu

et al. 2014

Gynecologic Oncology

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Objective Constitutive activation of STAT3 is a hallmark of various human cancers, although an increased pSTAT3 expression in high grade human endometrial cancer has not been reported. In the present study, we examine the expression of STAT family of proteins in endometrial cancer cell lines and the efficacy of HO-3867, a novel STAT3 inhibitor designed in our lab. Methods Expression of STAT family proteins was evaluated via western blot. The cell viability, post treatment with HO-3867, was assessed using MTT, cell-cycle profile and annexin assay. In vivo efficacy of HO-3867 was evaluated using xeonograft mice. Results Expression of activated STATs was inconsistent among the cell lines and 18 human endometrial cancer specimens tested. While pSTAT3 Tyr705 was not expressed in any of the cell lines, pSTAT3 Ser727 was highly expressed in endometrial cancer cell lines and tumor specimens. HO-3867 decreased the expression of pSTAT3 Ser727 while total STAT3 remained constant; cell viability decreased by 50–80% and induced G2/M arrest in 55% of Ishikawa cells at the G2/M cell cycle checkpoint. There was an increase in p53, a decrease in Bcl2 and Bcl-xL, and cleavage of caspase-3, caspase-7 and PARP. HO-3867 mediated a dosage-dependent inhibition of the growth of xenografted endometrial tumors. Conclusions HO-3867 treatment decreases the high levels of pSTAT3 Ser727 in endometrial cancer cells by inducing cell cycle arrest and apoptosis. This suggests a specific role of serine-phosphorylated STAT3, independent of tyrosine phosphorylation in the oncogenesis of endometrial cancer. HO-3867 could potentially serve as an adjunctive targeted therapy.

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Section: Discussionsupporting

confidence: 53%

Aberrantly activated pSTAT3-Ser727 in human endometrial cancer is suppressed by HO-3867, a novel STAT3 inhibitor

Tierney

McCann

Naidu

et al. 2014

Gynecologic Oncology

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“…Taken together, these results indicate that, downstream of the ERK pathway, the transcriptional regulation of miR-204 and miR-211 is different, with the latter being under the control of MITF, while the former is under the control of STAT3. The data also suggest-that JAK2, SRC and PI3K are all dispensable for the ERK pathway-dependent STAT3 activation [33]. …”

Section: Resultsmentioning

confidence: 99%

Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells

et al. 2017

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Despite increasing amounts of experimental evidence depicting the involvement of non-coding RNAs in cancer, the study of BRAFV600E-regulated genes has thus far focused mainly on protein-coding ones. Here, we identify and study the microRNAs that BRAFV600E regulates through the ERK pathway.By performing small RNA sequencing on A375 melanoma cells and a vemurafenib-resistant clone that was taken as negative control, we discover miR-204 and miR-211 as the miRNAs most induced by vemurafenib. We also demonstrate that, although belonging to the same family, these two miRNAs have distinctive features. miR-204 is under the control of STAT3 and its expression is induced in amelanotic melanoma cells, where it acts as an effector of vemurafenib's anti-motility activity by targeting AP1S2. Conversely, miR-211, a known transcriptional target of MITF, is induced in melanotic melanoma cells, where it targets EDEM1 and consequently impairs the degradation of TYROSINASE (TYR) through the ER-associated degradation (ERAD) pathway. In doing so, miR-211 serves as an effector of vemurafenib's pro-pigmentation activity. We also show that such an increase in pigmentation in turn represents an adaptive response that needs to be overcome using appropriate inhibitors in order to increase the efficacy of vemurafenib.In summary, we unveil the distinct and context-dependent activities exerted by miR-204 family members in melanoma cells. Our work challenges the widely accepted “same miRNA family = same function” rule and provides a rationale for a novel treatment strategy for melanotic melanomas that is based on the combination of ERK pathway inhibitors with pigmentation inhibitors.

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“…Previous studies have shown that phosphorylation of Serine 727 on STAT3 is required for full transcriptional responses. 27, 28, 46 Although IL6 production induced by mmLDL was intact in Raptor -deficient macrophages, IL6 signaling was decreased due to the reduced phosphorylation of its downstream target STAT3 at Ser727 which resulted in decreased mmLDL induced chemokine expression. Thus, the impact of macrophage mTORC1 activity was to amplify the effect of mmLDL/IL-6 on chemokine gene expression.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Mammalian Target of Rapamycin Complex 1 in Macrophages Decreases Chemokine Gene Expression and Atherosclerosis

Jiang

Westerterp

et al. 2014

Circulation Research

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Rationale The mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin, has been shown to decrease atherosclerosis, even while increasing plasma LDL levels. This suggests an anti-atherogenic effect possibly mediated by modulation of inflammatory responses in atherosclerotic plaques. Objective To assess the role of macrophage mTORC1 in atherogenesis. Methods and Results We transplanted bone marrow from mice in which a key mTORC1 adaptor, Raptor, was deleted in macrophages by Cre/loxP recombination (Mac-RapKO mice) into Ldlr-/- mice and then fed them the Western-type diet (WTD). Atherosclerotic lesions from Mac-RapKO mice showed decreased infiltration of macrophages, lesion size and chemokine gene expression compared with control mice. Treatment of macrophages with minimally modified LDL (mmLDL) resulted in increased levels of chemokine mRNAs and STAT3 phosphorylation; these effects were reduced in Mac-RapKO macrophages. While wild-type and Mac-RapKO macrophages showed similar STAT3 phosphorylation on Tyr705, Mac-RapKO macrophages showed decreased STAT3 Ser727 phosphorylation in response to mmLDL treatment and decreased Ccl2 promoter binding of STAT3. Conclusions The results demonstrate cross-talk between nutritionally-induced mTORC1 signaling and mmLDL-mediated inflammatory signaling via combinatorial phosphorylation of STAT3 in macrophages, leading to increased STAT3 activity on the CCL2 (MCP-1)promoter with pro-atherogenic consequences.

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Role and Regulation of STAT3 Phosphorylation at Ser727 in Melanocytes and Melanoma Cells

Cited by 89 publications

References 33 publications

Aberrantly activated pSTAT3-Ser727 in human endometrial cancer is suppressed by HO-3867, a novel STAT3 inhibitor

Aberrantly activated pSTAT3-Ser727 in human endometrial cancer is suppressed by HO-3867, a novel STAT3 inhibitor

Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells

Disruption of Mammalian Target of Rapamycin Complex 1 in Macrophages Decreases Chemokine Gene Expression and Atherosclerosis

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