A sesquiterpene lactone antrocin from Antrodia camphorata negatively modulates JAK2/STAT3 signaling via microRNA let-7c and induces apoptosis in lung cancer cells

Chi-Tai Yeh, Wen Chien Huang, Yerra Koteswara Rao, Min Ye, Wei Hwa Lee, Liang Shun Wang, David T W Tzeng, Chih Hsiung Wu, Yi Shing Shieh, Chi Ying F Huang, Yu Jen Chen, Michael Hsiao, Alexander T H Wu, Zhen Yang, Yew Min Tzeng

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51 Citations (Scopus)

Abstract

Lung cancer is the leading cause of cancer deaths worldwide and current therapies fail to treat this disease in majority of cases. Antrodia camphorata is a medicinal mushroom being widely used as food dietary supplement for cancer prevention. The sesquiterpene lactone antrocin is the most potent among >100 secondary metabolites isolated from A. camphorata. However, the molecular mechanisms of antrocin-mediated anticancer effects remain unclear. In this study, we found that antrocin inhibited cell proliferation in two non-small-cell lung cancer cells, namely H441 (wild-type epidermal growth factor receptor, IC50 = 0.75 μM) and H1975 (gefitnib-resistant mutant T790M, IC50 = 0.83 μM). Antrocin dose dependently suppressed colony formation and induced apoptosis as evidenced by activated caspase-3 and increased Bax/Bcl2 ratio. Gene profiling studies indicated that antrocin downregulated Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. We further demonstrated that antrocin suppressed both constitutively activated and interleukin 6-induced STAT3 phosphorylation and its subsequent nuclear translocation. Such inhibition is found to be achieved through the suppression of JAK2 and interaction between STAT3 and extracellular signal-regulated kinase. Additionally, antrocin increased microRNA let-7c expression and suppressed STAT signaling. The combination of antrocin and JAK2/STAT3 gene silencing significantly increased apoptosis in H441 cells. Such dual interruption of JAK2 and STAT3 pathways also induced downregulation of antiapoptotic protein mcl-1 and increased caspase-3 expression. In vivo intraperitoneal administration of antrocin significantly suppressed the growth of lung cancer tumor xenografts. Our results indicate that antrocin may be a potential therapeutic agent for human lung cancer cells through constitutive inhibition of JAK2/STAT3 pathway.

Original languageEnglish
Pages (from-to)2918-2928
Number of pages11
JournalCarcinogenesis
Volume34
Issue number12
DOIs
Publication statusPublished - Dec 2013

ASJC Scopus subject areas

  • Cancer Research

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    Yeh, C-T., Huang, W. C., Rao, Y. K., Ye, M., Lee, W. H., Wang, L. S., Tzeng, D. T. W., Wu, C. H., Shieh, Y. S., Huang, C. Y. F., Chen, Y. J., Hsiao, M., Wu, A. T. H., Yang, Z., & Tzeng, Y. M. (2013). A sesquiterpene lactone antrocin from Antrodia camphorata negatively modulates JAK2/STAT3 signaling via microRNA let-7c and induces apoptosis in lung cancer cells. Carcinogenesis, 34(12), 2918-2928. https://doi.org/10.1093/carcin/bgt255