Targeting transcription factor STAT3 for cancer prevention and therapy

Chai, Edna Zhi Pei; Shanmugam, Muthu K.; Arfuso, Frank; Wang, Chao; Kumar, Alan Prem; Samy, Ramar Perumal; Lim, Lina H.K.; Wang, Lingzhi; Goh, Boon Cher; Ahn, Kwang Seok; Hui, Kam M.; Sethi, Gautam

doi:10.1016/j.pharmthera.2015.10.004

Cited by 245 publications

(188 citation statements)

References 141 publications

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“…In particular, activation of Stat3 is known to be achieved through phosphorylation of its tyrosine 705 site by receptor tyrosine kinases (RTKs) and has been suggested to have a role in the progression of renal fibrosis (53)(54)(55). Although Stat3 activation from Sav1 loss alone was not obvious by Western blotting (data not shown), histological examination revealed an increase in phospho-…”

Section: Resultsmentioning

confidence: 97%

“…Cytokines such as interleukin-6 (Il6) are known to activate the signal transducers and activators of transcription (Stats) (53,54). In particular, activation of Stat3 is known to be achieved through phosphorylation of its tyrosine 705 site by receptor tyrosine kinases (RTKs) and has been suggested to have a role in the progression of renal fibrosis (53)(54)(55).…”

Section: Resultsmentioning

confidence: 99%

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Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Leung

Wilson

Voltzke

et al. 2017

Molecular and Cellular Biology

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Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of Sav1 in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of Sav1 induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from Sav1 loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Leung

Wilson

Voltzke

et al. 2017

Molecular and Cellular Biology

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“…33–39 Notably, previous studies have highlighted the critical roles of STAT3 signaling in tumor development and progression, indicating that suppression of STAT3 signaling may be a promising therapeutic target in many types of tumors. 40–44 We therefore clarified the role of STAT3 signaling in the possible molecular mechanisms of WWP1 in the progression of CSCC. We detected the expression levels of t-STAT3 and p-STAT3, as well as those of related proteins including MMP-2, Bcl-2 and cyclin D1 in CSCC A431 cells.…”

Section: Discussionmentioning

confidence: 99%

WW domain-containing E3 ubiquitin protein ligase 1 depletion evokes antitumor effect in cutaneous squamous cell carcinoma by inhibiting signal transducer and activator of transcription 3 signaling pathway

et al. 2018

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ObjectivesWW domain-containing E3 ubiquitin protein ligase 1 (WWP1) has been implicated in tumor progression. We aimed to investigate the role of WWP1 in cutaneous squamous cell carcinoma (CSCC).MethodsWWP1 gene and protein levels were detected using semi-quantitative reverse transcription-polymerase chain reaction, immunohistochemistry and western blotting. The effects of WWP1 on cell cycle, apoptosis, cell migration and invasion were examined by flow cytometry, wound healing and Transwell assays, respectively. The antitumor efficacy of WWP1 small interfering RNA was determined in CSCC tumor xenografts in mice.ResultsWWP1 expression was significantly higher in CSCC tissues and cells than in normal skin and cells, respectively. WWP1 expression was significantly associated with histological grade, invasion depth and lymph node metastasis in patients with CSCC. High expression predicted metastatic potential and an unfavorable prognosis. WWP1 downregulation suppressed tumor growth in vitro and in vivo, reduced cell migration and invasion, arrested the cell cycle in G0/G1 and induced apoptosis in A431 cells. WWP1 depletion also decreased phosphorylated signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase-2, cyclin D1 and Bcl-2, but did not affect total STAT3.ConclusionsWWP1 is a potential target for the diagnosis, prognosis and therapy of patients with CSCC.

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“…Indeed, there is a significant imbalance between MMPs and RECK, which serves as an important mechanism contributing to tumor progression with high grade lesions [8]. Many reports identified the oncogenic role of the protein signal transducer and the activator of transcription 3 (STAT3) in cancers, and STAT3 hyperactivation are known to be fundamentally important for metastasis [9-12]. Previous study reported RECK can control cancer metastasis by modulating STAT3-dependent neoangiogenic switch and STAT3 activation [13].…”

Section: Introductionmentioning

confidence: 99%

Suppression of Non-Small Cell Lung Cancer Growth and Metastasis by a Novel Small Molecular Activator of RECK

Shen¹,

Bang-hua²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Reversion-inducing cysteine-rich protein with kazal motifs (RECK) is a novel tumor suppressor gene that is critical for regulating tumor cell invasion and metastasis. The expression of RECK is dramatically down-regulated in human cancers. Harmine, a tricyclic compound from Peganum harmala, has been shown to have potential anti-cancer activity. Methods: Cell proliferation assay (CCK-8 cell viability assay), cell cycle analysis (detection by flow cytometry), apoptosis staining assay (TUNEL staining), cell migration assay and invasion assay (transwell assay) were carried out to investigate the Harmine’s efficacy on non-small cell lung cancer (NSCLC) cells in vitro. A549-luciferase cell orthotropic transplantation xenograft mouse model was used to determine the effect of Harmine treatment on NSCLC in vivo. Western blotting analysis of cell growth and metastasis related signal pathways was conducted to investigate the molecular mechanism of Harmine’s inhibitory effect on NSCLC. Results: Harmine treatment effectively inhibited cell proliferation and induced the G1/S cell cycle arrest of NSCLC cells. Further study proved that Harmine treatment led to apoptosis induction. Furthermore, treatment with NSCLC cells with Hamine resulted in decreased cell migration and cell invasion in vitro. More importantly, Harmine treatment significantly suppressed the NSCLC tumor growth and metastasis in mouse xenograft model in vivo. Mechanistically, in Harmine-treated NSCLC cells, RECK expression and its downstream signaling cascade were dramatically activated. As a consequence, the expression level of MMP-9 and E-cadherin were significantly decreased. Conclusion: These findings identify Harmine as a promising activator of RECK signaling for metastatic NSCLC treatment.

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Targeting transcription factor STAT3 for cancer prevention and therapy

Cited by 245 publications

References 141 publications

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

WW domain-containing E3 ubiquitin protein ligase 1 depletion evokes antitumor effect in cutaneous squamous cell carcinoma by inhibiting signal transducer and activator of transcription 3 signaling pathway

Suppression of Non-Small Cell Lung Cancer Growth and Metastasis by a Novel Small Molecular Activator of RECK

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