Oncotarget

Research Papers:

Physalin A exerts anti-tumor activity in non-small cell lung cancer cell lines by suppressing JAK/STAT3 signaling

Fanfan Zhu, Chunyan Dai, Yufei Fu, Jacky F.C. Loo, Dajin Xia, Sizhi P. Gao, Zhongjun Ma and Zhe Chen _

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Oncotarget. 2016; 7:9462-9476. https://doi.org/10.18632/oncotarget.7051

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Abstract

Fanfan Zhu1,*, Chunyan Dai1,*, Yufei Fu1,*, Jacky F.C. Loo2, Dajin Xia3, Sizhi P. Gao4, Zhongjun Ma5, Zhe Chen1

1Zhejiang Key Laboratory of Gastro-Intestinal Pathophysiology, Zhejiang Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, PR China

2Biochemistry Program, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong

3Zhejiang University School of Public Health, Zijingang Campus, Hangzhou, PR China

4HOPP, Memorial Sloan Kettering Cancer Center, New York, NY, USA

5Institute of Marine Biology and Natural Products, Ocean College, Zhejiang University, Zijingang Campus, Hangzhou, PR China

*These authors have contributed equally to this work

Correspondence to:

Zhe Chen, e-mail: chenzhe@zju.edu.cn

Zhongjun Ma, e-mail: mazj@zju.edu.cn

Sizhi P. Gao, e-mail: gaos@mskcc.org

Keywords: JAK/STAT3, non-small cell lung cancer, physalin A, withanolide

Received: August 10, 2015     Accepted: January 01, 2016     Published: January 28, 2016

ABSTRACT

The signal transducers and activators of transcription 3 (STAT3) signaling pathway plays critical roles in the pathogenesis and progression of various human cancers, including non-small cell lung cancer (NSCLC). In this study, we aimed to evaluate the therapeutic potential of physalin A, a bioactive withanolide derived from Physalis alkekengi var. francheti used in traditional Chinese medicine, was evaluated in human NSCLC cells. Its and determined whether it effect oninhibited both constitutive and induced STAT3 activity, through repressing the phosphorylation levels of JAK2 and JAK3, resulting in anti-proliferation and pro-apoptotic effects on NSCLC cells was also determined, and. theThe antitumor effects of physalin A were also validated usingin an in vivo mouse xenograft models of NSCLC cells. Physalin A had anti-proliferative and pro-apoptotic effects in NSCLC cells with constitutively activated STAT3; it also suppressed both constitutive and induced STAT3 activity by modulating the phosphorylation of JAK2 and JAK3. Furthermore, physalin A abrogated the nuclear translocation and transcriptional activity of STAT3, thereby decreasing the expression levels of STAT3, its target genes, such as Bcl-2 and XIAP. Knockdown of STAT3 expression by small interfering RNA (siRNA) significantly enhanced the pro-apoptotic effects of physalin A in NSCLC cells. Moreover, physalin A significantly suppressed tumor xenograft growth. Thus, as an inhibitor of JAK2/3-STAT3 signaling, physalin A, has potent anti-tumor activities, which may facilitate the development of a therapeutic strategy for treating NSCLC.


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