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.