A sesquiterpene lactone antrocin from Antrodia camphorata negatively modulates JAK2/STAT3 signaling via microRNA let-7c and induces apoptosis in lung cancer cells
A sesquiterpene lactone antrocin from Antrodia camphorata negatively modulates JAK2/STAT3 signaling via microRNA let-7c and induces apoptosis in lung cancer cells
复制标题
牛樟芝中的倍半萜内酯 antrocin 通过 microRNA let-7c 负调节 JAK2/STAT3 信号传导并诱导肺癌细胞凋亡
DOI：
10.1093/carcin/bgt255
复制
发表时间：
2013-12-01
期刊：
影响因子：
4.7
通讯作者：
Tzeng, Yew-Min
中科院分区：
文献类型：
--
作者：
Yeh, Chi-Tai;Huang, Wen-Chien;Tzeng, Yew-Min
肺癌是世界范围内癌症死亡的主要原因，目前的疗法在大多数情况下无法治疗这种疾病。牛樟芝是一种药用蘑菇，被广泛用作预防癌症的食品膳食补充剂。倍半萜内酯antrocin是从A. camphorata.然而，Antrocin介导的抗癌作用的分子机制仍不清楚。在这项研究中，我们发现，antrocin抑制两个非小细胞肺癌细胞，即H441（野生型表皮生长因子受体，IC 50 = 0.75 μ M）和H1975（吉非替尼耐药突变体T790 M，IC 50 = 0.83 μ M）的细胞增殖。Antrocin剂量依赖性地抑制集落形成并诱导细胞凋亡，如通过激活caspase-3和增加Bax/Bcl 2比率所证明的。基因表达谱研究表明，antrocin下调Janus激酶/信号转导和转录激活因子（JAK/STAT）信号通路。我们进一步证明，antrocin抑制组成性激活和白细胞介素6诱导的STAT 3磷酸化及其随后的核转位。这种抑制作用是通过抑制JAK 2和STAT 3与细胞外信号调节激酶之间的相互作用来实现的。此外，antrocin增加microRNA let-7 c表达并抑制STAT信号传导。Antrocin联合JAK 2/STAT 3基因沉默可显著增加H441细胞的凋亡。JAK 2和STAT 3通路的这种双重中断也诱导抗凋亡蛋白mcl-1的下调和caspase-3表达的增加。在体内腹腔注射antrocin显着抑制肺癌肿瘤异种移植物的生长。我们的研究结果表明，antrocin可能是一个潜在的治疗剂，通过组成性抑制JAK 2/STAT 3途径的人肺癌细胞。
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 mu M) and H1975 (gefitnib-resistant mutant T790M, IC50 = 0.83 mu M). 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.