The JAK/STAT3 axis: A comprehensive drug target for solid malignancies

Huynh, Jennifer; Etemadi, Nima; Hollande, Frédéric; Ernst, Matthias; Büchert, Michael

doi:10.1016/j.semcancer.2017.06.001

Cited by 157 publications

(126 citation statements)

References 138 publications

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“…These results demonstrated that STAT3 activation by W4P-LHB can be reversed by CDDO-me. Facilitation of tumor growth by STAT3 activation was mediated by cyclin D1 expression and suppression of p53 expression [23][24][25]. As expected, the protein level of cyclin D1 in NIH3T3-W4P was drastically decreased by CDDO-me treatment in a dose-dependent manner (Fig.…”

Section: Suppression Of Stat3 Activation By Cddo-me In Nih3t3-w4p Celsupporting

confidence: 75%

Bardoxolone Methyl Suppresses Hepatitis B Virus Large Surface Protein Variant W4P-Related Carcinogenesis and Hepatocellular Carcinoma Cell Proliferation Via the Inhibition of Signal Transducer and Activator of Transcription 3 Signaling

et al. 2018

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Bardoxolone methyl (CDDO-me) is a synthetic triterpenoid that has been shown to suppress various cancers and inflammation. It has been implicated for the suppression of signal transducer and activator of transcription 3 (STAT3)-mediated signaling, which plays crucial roles in the development and progression of hepatocellular carcinoma (HCC). Previously, we showed that hepatitis B virus (HBV) large surface protein (LHB) variant W4P promotes carcinogenesis and tumor progression through STAT3 activation. Thus, we examined the anti-cancer activity of CDDO-me against HCC using W4P-LHB-expressing NIH3T3 cells and HepG2 and Huh7 HCC cell lines. CDDO-me exerted cytotoxic activity against W4P-LHB-expressing NIH3T3 cells, HepG2 cells, and Huh7 cells, and induced apoptotic cell death in a dose-dependent manner, demonstrating its anti-cancer activity against HCC. Sublethal concentrations of CDDO-me suppressed STAT3 activation by W4P-LHB ectopic expression and interleukin-6 treatment in W4P-LHB-NIH3T3 and Huh7 cells respectively. The suppression of STAT3 activation by CDDO-me in W4P-LHB-NIH3T3 cells was further confirmed by decreased cyclin D1 protein levels and increased p21 and p53 mRNA synthesis. In addition, CDDO-me treatment resulted in decreased cell migration and colony formation in in vitro assays using W4P-LHB-NIH3T3, HepG2, or Huh7 cell lines, supporting its anti-cancer activity through STAT3 inhibition. Furthermore, CDDO-me administration significantly suppressed tumor growth induced by W4P-LHB-expressing NIH3T3 cells in nude mice, confirming its anti-cancer activity. Collectively, our findings demonstrated that CDDO-me is capable of suppressing STAT3 activation in HCC cells and cells transformed by the natural variant of HBV protein. The results suggest that CDDO-me can be a potential therapeutic agent against HCC, especially tumors related to HBV mutations.

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Section: Suppression Of Stat3 Activation By Cddo-me In Nih3t3-w4p Celsupporting

confidence: 75%

Bardoxolone Methyl Suppresses Hepatitis B Virus Large Surface Protein Variant W4P-Related Carcinogenesis and Hepatocellular Carcinoma Cell Proliferation Via the Inhibition of Signal Transducer and Activator of Transcription 3 Signaling

et al. 2018

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“…And interleukin 6 and interleukin 10 can act as upstream mediators of STAT3 (Huynh et al . ). However, it remains unclear whether the underlying mechanisms of Sals on angiogenesis are related to these factors.…”

Section: Discussionmentioning

confidence: 97%

Salvianolic acids enhance cerebral angiogenesis and neurological recovery by activating JAK2/STAT3 signaling pathway after ischemic stroke in mice

Zhang

Cui

et al. 2017

Journal of Neurochemistry

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Post-stroke angiogenesis facilitates neurovascular remodeling process and promotes neurological recovery. Proangiogenic effects of Salvianolic acids (Sals) have been reported in various ischemic disorders. However, the underlying mechanisms are still poorly understood. Previous studies of our laboratory have demonstrated that activating Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway is involved in the protection against cerebral ischemia/reperfusion injury. In this study, we investigated the impacts of Sals on angiogenesis and long-term neurological recovery after ischemic stroke as well as the potential mechanisms. Male mice subjected to permanent distal middle cerebral artery occlusion were administrated with Sals, 5-bromo-2'-deoxyuridine, and JAK2 inhibitor AG490 once daily from day 1 to day 14 after distal middle cerebral artery occlusion. Compared with the control group, Sals treatment significantly improved neurological recovery at day 14 and 28 after ischemic stroke. Sals enhanced post-stroke angiogenesis, pericytes and astrocytic endfeet covered ratio in the peri-infarct area. The JAK2/STAT3 signaling pathway was activated by Sals in the angiogenesis process, and inhibition of JAK2/STAT3 signaling blocked the effects of Sals on post-stroke angiogenesis and neurological recovery as well as abolished the mediation of proangiogenic factors. In summary, these data suggest that Sals administration enhances cerebral angiogenesis and promotes neurological recovery after ischemic stroke, mediated by the activation of JAK2/STAT3 signaling pathway.

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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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The JAK/STAT3 axis: A comprehensive drug target for solid malignancies

Cited by 157 publications

References 138 publications

Bardoxolone Methyl Suppresses Hepatitis B Virus Large Surface Protein Variant W4P-Related Carcinogenesis and Hepatocellular Carcinoma Cell Proliferation Via the Inhibition of Signal Transducer and Activator of Transcription 3 Signaling

Bardoxolone Methyl Suppresses Hepatitis B Virus Large Surface Protein Variant W4P-Related Carcinogenesis and Hepatocellular Carcinoma Cell Proliferation Via the Inhibition of Signal Transducer and Activator of Transcription 3 Signaling

Salvianolic acids enhance cerebral angiogenesis and neurological recovery by activating JAK2/STAT3 signaling pathway after ischemic stroke in mice

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

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