Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling

Zhang, Xing; Lu, Hong; Hong, Weilong; Liu, Leping; Wang, Silu; Zhou, Mengtao; Chen, Bicheng; Bai, Yongheng

doi:10.3892/or.2018.6241

Cited by 10 publications

(10 citation statements)

References 33 publications

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“…Assuming that STAT3 inactivation participates in Stattic-induced inhibition of pancreatic cancer cell metastasis, we next sought to determine whether activating STAT3 reverses the antineoplastic effects of Stattic. First, we treated cells using IL-6, a STAT3 agonist [39]. As expected, IL-6 not only induced JAK2 phosphorylation in PANC-1 and BxPc-3 cells after Stattic treatment, but also promoted STAT3 phosphorylation (Fig.…”

Section: Activating Stat3 Abolishes Stattic-mediated Inhibition Of Pcc Invasion and Migration Independent Of Tgf-β/smad Signalingsupporting

confidence: 61%

Pharmacological Inhibition of STAT3 Attenuates Pancreatic Cancer Cell Invasion and Migration By Interacting with TGF-Β/Smad Signaling

Guo

Xiao

Yang

et al. 2021

Preprint

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Background Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with extremely poor prognosis, primarily due to the infiltration and metastasis of tumor cells. Many studies have shown that the TGF-β/Smad signaling-mediated EMT pathway is a key driving factor of infiltration and metastasis of pancreatic cancer cells, and aberrant STAT3 activation is vital to pancreatic cancer cell metastasis. In this study, a small molecule antagonist, Stattic, was used for targeted STAT3 inhibition, its interaction with TGF-β/Smad signaling was observed, and EMT of pancreatic cancer cells was inhibited to decrease its metastasis and infiltration. Methods The effects of Stattic on the invasion, infiltration, and EMT of pancreatic cancer cells were studied. We also evaluated the effects of Stattic on the STAT3 and TGF-β/Smad signaling pathways and studied the interactions between STAT3 and TGF-β/Smad signaling using overexpression and siRNA techniques. Results Stattic inhibited the invasion and infiltration of pancreatic cancer cells in a dose- and time-dependent manner, which was related to EMT inhibition and subsequent downregulation of extracellular matrix components. Stattic downregulated the expression of metalloproteases, such as MMP-2, and also inhibited the expression of EMT-TFs, such as Snail1 and Slug, and downregulated downstream HIF1α and VEGF expression to inhibit angiogenesis. Mechanistically, in in vitro cell models and in vivo nude mouse tumorigenicity models, Stattic treatment significantly downregulated the protein levels of the matrix synthesis-promoting factor TGF-β and the phosphorylation and nuclear import of its downstream Smad2/3. These results suggest that Stattic inactivates TGF-β/Smad signaling to antagonize EMT and eventually inhibit the invasion and infiltration of pancreatic cancer cells. Stattic is a small molecule inhibitor of STAT3 that can downregulate STAT3 activity, which is enhanced by Smad4-dependent TGF-β/Smad signaling. Interestingly, IL-6 or STAT3 overexpression promotes EMT but in a non-TGF-β/Smad-dependent manner, and is regulated by antagonism between STAT3 and Smad4. Conclusions The application of Stattic pharmacologically to inhibit STAT3 decreases the invasion and infiltration of pancreatic cancer cells, which may be achieved through interactions with TGF-β/Smad signaling and EMT antagonism.

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Section: Activating Stat3 Abolishes Stattic-mediated Inhibition Of Pcc Invasion and Migration Independent Of Tgf-β/smad Signalingsupporting

confidence: 61%

Pharmacological Inhibition of STAT3 Attenuates Pancreatic Cancer Cell Invasion and Migration By Interacting with TGF-Β/Smad Signaling

Guo

Xiao

Yang

et al. 2021

Preprint

Self Cite

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“…E-cadherin, N-cadherin and ZEB2 are generally regarded as the downstream molecules of the JAK2/STAT3 signaling pathway [ 29 – 31 ]. Several studies have shown that JAK2/STAT3 can be activated by several chemokines including CXCL3, CCL20, CXCL9, and IL-6 [ 32 – 35 ]. However, the interplay between CCL18 and the JAK2/STAT3 signaling pathway remains unknown.…”

Section: Discussionmentioning

confidence: 99%

CCL18-NIR1 promotes oral cancer cell growth and metastasis by activating the JAK2/STAT3 signaling pathway

et al. 2020

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Background Chemokine (C-C motif) ligand 18 (CCL18) affects the malignant progression of varying cancers by activating chemokine receptors. Our previous work has shown that CCL18 promotes hyperplasia and invasiveness of oral cancer cells; however, the cognate receptors of CCL18 involved in the pathogenesis of oral squamous cell carcinoma (OSCC) have not yet been identified. This study aimed to investigate the molecular mechanisms which underlie promotive effects of CCL18 on OSCC progression by binding to functional receptors. Methods The expression of CCL18 receptor-NIR1 in OSCC was determined by conducting western blot, immunofluorescence, and immunocytochemistry assays. Chi square test was applied to analyze the relationship between expression levels of NIR1 and clinicopathological variables. Recombinant CCL18 (rCCL18), receptor siRNA and JAK specific inhibitor (AG490) were used in experiments investigating the effects of the CCL18-NIR1 axis on growth of cancer cells (i.e., proliferation, and metastasis), epithelial-mesenchymal transition (EMT) and the activation of the JAK2/STAT3 signaling pathway. Results NIR1 as functional receptor of CCL18 in OSCC, was found to be significantly upregulated in OSCC and positively related to the TNM stage of OSCC patients. rCCL18 induced the phenotypical alterations in oral cancer cells including cell growth, metastasis and EMT. The JAK2/STAT3 signaling pathway was confirmed to be a downstream pathway mediating the effects of CCL18 in OSCC. AG490 and knockdown of NIR1 could block the effects of rCCL18-induced OSCC. Conclusion CCL18 can promote the progression of OSCC by binding NIR1, and the CCL18-NIR1 axis can activate JAK2/STAT3 signaling pathway. The identification of the mechanisms underlying CCL18-mediated promotion of OSCC progression could highlight potential therapeutic targets for treating oral cancer.

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“…In cells, ARF6 recycles between GTP-bound (active) and GDP-bound (inactive) forms that are regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) [4]. In humans, 15 GEFs have been con rmed and sorted into 6 families (Cytohesin 1-4, EFA6A-D, BRAG1-3, BIG1/2, GBF, FBX8). All GEFs have a common Sec7 domain.…”

Section: Introductionmentioning

confidence: 99%

ARF6 promotes hepatocellular carcinoma proliferation through activating STAT3 signaling

Huang

Xie

et al. 2023

Preprint

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Purpose Hepatocellular Carcinoma (HCC) is one of the most common causes of cancer death worldwide. However, the molecular mechanism underlying HCC proliferation remains obscure. In this study, we show that high expression of ARF6 is related to a poor clinical prognosis, which could drive the proliferation of HCC. Methods The expression level of ARF6 in HCC tissues was detected by immunohistochemistry and western blotting. Clinical significance of ARF6 was estimated in primary HCC patients. The effect of ARF6 on tumor proliferation was investigated by in vitro CCK8 and colony formation assay, and in vivo nude mouse xenograft models. ARF6 localization was investigated by immunofluorescence. Cell cycle-related proteins were evaluated by western blotting. Moreover, the correlation between ARF6 and STAT3 signaling in HCC was detected by western blotting, immunohistochemistry and xenograft assay. Results ARF6 was overexpressed in HCC tissues compared to adjacent normal liver tissues and high expression of ARF6 was significantly correlated with poor tumor differentiation, incomplete tumor encapsulation, advanced tumor TNM stage and poor prognosis. ARF6 positively regulated the cell proliferation, colony formation, and cell cycle progression of HCC cells. In vivo nude mouse xenograft models proved the oncogenic role of ARF6 in tumor growth. In addition, ARF6 promoted the activation of STAT3 signaling and ARF6 expression was positively correlated with phosphorylated STAT3 in HCC tissues. Furthermore, interference of STAT3 demonstrated STAT3 as an important signaling pathway for the oncogenic role of ARF6 in HCC. Conclusions Our findings indicate that ARF6 promotes HCC proliferation through activating STAT3 signaling, suggesting that ARF6 may serve as a novel prognostic biomarker and a therapeutic target for HCC patients.

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Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling

Cited by 10 publications

References 33 publications

Pharmacological Inhibition of STAT3 Attenuates Pancreatic Cancer Cell Invasion and Migration By Interacting with TGF-Β/Smad Signaling

Pharmacological Inhibition of STAT3 Attenuates Pancreatic Cancer Cell Invasion and Migration By Interacting with TGF-Β/Smad Signaling

CCL18-NIR1 promotes oral cancer cell growth and metastasis by activating the JAK2/STAT3 signaling pathway

ARF6 promotes hepatocellular carcinoma proliferation through activating STAT3 signaling

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