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

Research output: Contribution to journalArticle

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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

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Antrodia
Sesquiterpenes
Lactones
MicroRNAs
Lung Neoplasms
Apoptosis
Dietary Supplements
Caspase 3
Inhibitory Concentration 50
Down-Regulation
antrocin
Janus Kinases
Neoplasms
Agaricales
Extracellular Signal-Regulated MAP Kinases
Gene Silencing
Transducers
Epidermal Growth Factor Receptor
Heterografts
Non-Small Cell Lung Carcinoma

ASJC Scopus subject areas

  • Cancer Research

Cite this

A sesquiterpene lactone antrocin from Antrodia camphorata negatively modulates JAK2/STAT3 signaling via microRNA let-7c and induces apoptosis in lung cancer cells. / Yeh, Chi-Tai; Huang, Wen Chien; Rao, Yerra Koteswara; Ye, Min; Lee, Wei Hwa; Wang, Liang Shun; Tzeng, David T W; Wu, Chih Hsiung; Shieh, Yi Shing; Huang, Chi Ying F; Chen, Yu Jen; Hsiao, Michael; Wu, Alexander T H; Yang, Zhen; Tzeng, Yew Min.

In: Carcinogenesis, Vol. 34, No. 12, 12.2013, p. 2918-2928.

Research output: Contribution to journalArticle

Yeh, C-T, Huang, WC, Rao, YK, Ye, M, Lee, WH, Wang, LS, Tzeng, DTW, Wu, CH, Shieh, YS, Huang, CYF, Chen, YJ, Hsiao, M, Wu, ATH, Yang, Z & Tzeng, YM 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, vol. 34, no. 12, pp. 2918-2928. https://doi.org/10.1093/carcin/bgt255
Yeh, Chi-Tai ; Huang, Wen Chien ; Rao, Yerra Koteswara ; Ye, Min ; Lee, Wei Hwa ; Wang, Liang Shun ; Tzeng, David T W ; Wu, Chih Hsiung ; Shieh, Yi Shing ; Huang, Chi Ying F ; Chen, Yu Jen ; Hsiao, Michael ; Wu, Alexander T H ; Yang, Zhen ; Tzeng, Yew Min. / A sesquiterpene lactone antrocin from Antrodia camphorata negatively modulates JAK2/STAT3 signaling via microRNA let-7c and induces apoptosis in lung cancer cells. In: Carcinogenesis. 2013 ; Vol. 34, No. 12. pp. 2918-2928.
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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.",
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AU - Rao, Yerra Koteswara

AU - Ye, Min

AU - Lee, Wei Hwa

AU - Wang, Liang Shun

AU - Tzeng, David T W

AU - Wu, Chih Hsiung

AU - Shieh, Yi Shing

AU - Huang, Chi Ying F

AU - Chen, Yu Jen

AU - Hsiao, Michael

AU - Wu, Alexander T H

AU - Yang, Zhen

AU - Tzeng, Yew Min

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N2 - 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.

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