ATF3 reduces migration capacity by regulation of matrix metalloproteinases via NFκB and STAT3 inhibition in glioblastoma

Guenzle, Jessica; Wolf, Louisa J; Garrelfs, Nicklas W C; Goeldner, Jonathan M; Osterberg, Nadja; Schindler, Cora Rebecca; Saavedra, Joseph E.; Weyerbrock, Astrid

doi:10.1038/cddiscovery.2017.6

Cited by 26 publications

(23 citation statements)

References 60 publications

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“…Finally, cell proliferation was monitored by 5′-bromodeoxyuridine (BrdU) incorporation assay (Roche Diagnostics, Mannheim, Germany). Three thousand cells were cultured for 24 and 48 hours in 96-well plates and stained with BrdU as previously described [32] . The percentage of cells exhibiting genomic BrdU incorporation was measured by absorbance at 370 nm with Tecan Infinite200 (Tecan, Männedorf, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of mTORC2/RICTOR Impairs Melanoma Hepatic Metastasis

et al. 2018

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Mammalian target of rapamycin complex 2 (mTORC2) with its pivotal component rapamycin-insensitive companion of mTOR (RICTOR) is the major regulator of AKT phosphorylation and is increasingly implicated in tumor growth and progression. In cutaneous melanoma, an extremely aggressive and highly metastatic disease, RICTOR overexpression is involved in tumor development and invasiveness. Therefore, we investigated the impact of RICTOR inhibition in melanoma cells in vitro and in vivo with special emphasis on hepatic metastasis. Moreover, our study focused on the interaction of tumor cells and hepatic stellate cells (HSC) which play a crucial role in the hepatic microenvironment. In silico analysis revealed increased RICTOR expression in melanoma cells and tissues and indicated higher expression in advanced melanoma stages and metastases. In vitro, transient RICTOR knock-down via siRNA caused a significant reduction of tumor cell motility. Using a syngeneic murine splenic injection model, a significant decrease in liver metastasis burden was detected in vivo. Moreover, stimulation of melanoma cells with conditioned medium (CM) from activated HSC or hepatocyte growth factor (HGF) led to a significant induction of AKT phosphorylation and tumor cell motility. Blocking of RICTOR expression in cancer cells diminished constitutive and HGF-induced AKT phosphorylation as well as cell motility. Interestingly, RICTOR blockade also led to an abrogation of CM-induced effects on AKT phosphorylation and motility in melanoma cells. In conclusion, these results provide first evidence for a critical role of mTORC2/RICTOR in melanoma liver metastasis via cancer cell/HSC interactions.

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Section: Methodsmentioning

confidence: 99%

Inhibition of mTORC2/RICTOR Impairs Melanoma Hepatic Metastasis

et al. 2018

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“…Activating transcription factor 3 (ATF3), an ATF/cAMP-responsive element-binding protein (CREB) family member, was found to be involved in a broad spectrum of cellular stresses, including DNA damage [ 3 ], cellular injury [ 4 ], oxidative stress and oncogenic stimuli [ 5 ], and was also shown to regulate diverse cellular functions by either binding to the ATF/CREB cis-regulatory element or interacting with other proteins, such as p53 and NF-κB [ 6 ]. Several reports indicated that ATF3 expression is downregulated in a variety of human cancers, including colon cancer [ 7 ], liver cancer [ 8 ], multiple myeloma [ 9 ], neuroblastoma [ 10 ], bladder cancer [ 11 ], prostate cancer [ 12 ], malignant glioma [ 13 ] and non-small cell lung carcinoma [ 14 ]. ATF3 may inhibit tumor formation by inducing cell cycle arrest and apoptosis [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

ATF3 inhibits the tumorigenesis and progression of hepatocellular carcinoma cells via upregulation of CYR61 expression

Chen

Liu

et al. 2018

J Exp Clin Cancer Res

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BackgroundHepatocellular carcinoma (HCC) is one of the most common malignant cancers with a high incidence and high mortality in East Asia. Identifying biomarkers and clarifying the regulatory mechanisms of HCC are of great importance. Herein, we report the role and mechanism of activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element-binding protein family of transcription factors in HCC.MethodsATF3 overexpression vector and shRNAs were transfected into HCC cancer cells to upregulate or downregulate ATF3 expression. In vitro and in vivo assays were performed to investigate the functional role of ATF3 in hepatocellular carcinoma. RNA-Seq was performed to screen the differentially expressed genes downstream of ATF3. The dual-luciferase reporter assay, chromatin immunoprecipitation (Ch-IP) analysis and functional rescue experiments were used to confirm the target gene regulated by ATF3. Tissue microarrays (TMAs) comprising 236 human primary HCC tissues were obtained and immunohistochemical staining were carried out to analyze the clinical significance of ATF3.ResultsThe results indicate that ATF3 significantly inhibited the proliferation and mobility of HCC cells both in vitro and in vivo. Cysteine-rich angiogenic inducer 61 (CYR61) is a key target for transcriptional regulation by ATF3. Both ATF3 and CYR61 were consistently downregulated in human HCC tissues, and their expression levels were significantly and positively correlated with each other.ConclusionsOur findings indicate that ATF3 functions as a tumor suppressor in HCC through targeting and regulating CYR61.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0919-8) contains supplementary material, which is available to authorized users.

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“…MMP and TIMP genes have been shown to regulate cancer cell invasion, and ATF3 is reported to reduce the ability to migrate by regulating the MMP and TIMP expression in human glioblastoma cells [ 55 ]. To address if ATF3 regulates the expression of MMPs or TIMPs in HCT116 cells, we performed PCR array analysis of Chan’s β-catWT, β-catMut, and β-catMut cells after ATF3-knockdown.…”

Section: Resultsmentioning

confidence: 99%

The stress response gene ATF3 is a direct target of the Wnt/β-catenin pathway and inhibits the invasion and migration of HCT116 human colorectal cancer cells

et al. 2018

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Aberrant Wnt/β-catenin signaling is implicated in tumorigenesis and the progression of human colorectal cancers, and mutations in the components of the Wnt/β-catenin signaling pathway are observed in the majority of patients. Therefore, extensive studies on the Wnt signaling pathway and its target genes are crucial to understand the molecular events of tumorigenesis and develop an efficacious therapy. In this study, we showed that the stress response gene ATF3 is transcriptionally activated by the binding of β-catenin and TCF4 to the redundant TCF4 site at the proximal promoter region of the ATF3 gene, indicating that ATF3 is a direct target of the Wnt/β-catenin pathway. The loss of function or overexpression studies showed that ATF3 inhibited the migration or invasion of HCT116 cells. The expression of some MMP and TIMP genes and the ratio of MMP2/9 to TIMP3/4 mRNAs was differentially regulated by ATF3. Therefore, though ATF3 is activated downstream of the Wnt/β-catenin pathway, it acts as a negative regulator of the migration and invasion of HCT116 human colon cancer cells exhibiting aberrant Wnt/β-catenin activity. ATF3 is a candidate biomarker and target for human colorectal cancer treatment and prevention.

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ATF3 reduces migration capacity by regulation of matrix metalloproteinases via NFκB and STAT3 inhibition in glioblastoma

Cited by 26 publications

References 60 publications

Inhibition of mTORC2/RICTOR Impairs Melanoma Hepatic Metastasis

Inhibition of mTORC2/RICTOR Impairs Melanoma Hepatic Metastasis

ATF3 inhibits the tumorigenesis and progression of hepatocellular carcinoma cells via upregulation of CYR61 expression

The stress response gene ATF3 is a direct target of the Wnt/β-catenin pathway and inhibits the invasion and migration of HCT116 human colorectal cancer cells

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