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XZH-5 inhibits STAT3 phosphorylation and causes apoptosis in human hepatocellular carcinoma cells

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Abstract

Growing evidence has demonstrated that signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in patients with hepatocellular carcinoma (HCC), plays an important role in HCC development, progression, and prognosis. Interleukin-6 (IL-6) is a multifunctional inflammatory cytokine, which may induce STAT3 activation in a variety of human cancers. In this study, we demonstrated that blocking STAT3 phosphorylation with STAT3 small molecule inhibitors SD-1029 and Stattic caused apoptosis in HCC cells. Then we characterized the inhibitory effects of a novel small molecule XZH-5 on STAT3 phosphorylation in HCC cell lines. XZH-5 reduced constitutive STAT3 phosphorylation at Tyr705 and the expression of STAT3 downstream genes. The inhibition of STAT3 in HCC cells resulted in the induction of apoptosis and reduction of colony forming ability. In addition, XZH-5 also inhibited IL-6-induced STAT3 phosphorylation, nuclear translocation and STAT3 DNA binding activity. In contrast, it had no effect on IFN-γ-induced STAT1 phosphorylation, indicating the more selective effects on STAT3. These results suggested that XZH-5 may serve as a lead compound for further development of STAT3 specific small molecule inhibitors for HCC therapy.

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Acknowledgment

This study was partly supported by a grant from NIHR21 to Jiayuh Lin.

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Author notes

  1. Yan Liu

    Present address: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

Authors and Affiliations

  1. Center for Childhood Cancer, Department of Pediatrics, College of Medicine, The Ohio State University, 700 Children’s Drive, Columbus, OH, 43205, USA

    Yan Liu, Aiguo Liu & Jiayuh Lin

  2. Department of Chemistry and Biochemistry, Miami University, Oxford, OH, USA

    Zhenghu Xu & Hong Wang

  3. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Wenying Yu & Chenglong Li

  4. Department of Pediatrics, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China

    Aiguo Liu

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  1. Yan Liu
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Correspondence to Jiayuh Lin.

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Yan Liu, Aiguo Liu contributed equally.

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Liu, Y., Liu, A., Xu, Z. et al. XZH-5 inhibits STAT3 phosphorylation and causes apoptosis in human hepatocellular carcinoma cells. Apoptosis 16, 502–510 (2011). https://doi.org/10.1007/s10495-011-0578-0

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  • DOI: https://doi.org/10.1007/s10495-011-0578-0

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