title: A sesquiterpene lactone antrocin from Antrodia camphorata negatively modulates JAK2/STAT3 signaling via microRNA let-7c and induces apoptosis in lung cancer cells.
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.
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Yeh
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Huang
authors.forename: Yerra Koteswara
authors.initials: YK
authors.lastname: Rao
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.forename: Wei-Hwa
authors.initials: WH
authors.lastname: Lee
authors.forename: Liang-Shun
authors.initials: LS
authors.lastname: Wang
authors.forename: David T W
authors.initials: DT
authors.lastname: Tzeng
authors.forename: Chih-Hsiung
authors.initials: CH
authors.lastname: Wu
authors.forename: Yi-Shing
authors.initials: YS
authors.lastname: Shieh
authors.forename: Chi-Ying F
authors.initials: CY
authors.lastname: Huang
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Alexander T H
authors.initials: AT
authors.lastname: Wu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.forename: Yew-Min
authors.initials: YM
authors.lastname: Tzeng
mesh_terms: D000363:Agaricales / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D055491:Antrodia / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D007783:Lactones; C579095:MCL1 protein, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D012717:Sesquiterpenes; C558369:antrocin; D051028:bcl-2-Associated X Protein; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D051562:Proto-Oncogene Proteins c-bcr; D053148:Caspase 3