Inhibition of JAK2/STAT3 signalling induces colorectal cancer cell apoptosis via mitochondrial pathway.
Inhibition of JAK2/STAT3 signalling induces colorectal cancer cell apoptosis via mitochondrial pathway.
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抑制JAK2/STAT3信号通过线粒体途径诱导结直肠癌细胞凋亡
DOI：
10.1111/j.1582-4934.2011.01483.x
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发表时间：
2012-08
影响因子：
5.3
通讯作者：
Fang JY
中科院分区：
文献类型：
--
作者：
Du W;Hong J;Wang YC;Zhang YJ;Wang P;Su WY;Lin YW;Lu R;Zou WP;Xiong H;Fang JY
JAK 2/STAT 3通路的异常参与了结直肠癌（CRC）的发病机制，包括细胞凋亡。然而，JAK 2/STAT 3信号转导失调导致细胞凋亡的确切机制尚未阐明。为了研究JAK 2和STAT 3在CRC凋亡机制中的作用，我们用AG 490抑制JAK 2，用小干扰RNA耗尽STAT 3。我们的数据表明，JAK 2/STAT 3信号转导抑制通过调节Bcl-2基因家族，促进线粒体跨膜电位（Δ Km）的丧失和活性氧的增加诱导CRC细胞凋亡。此外，我们的研究结果表明，细胞色素c（Cyt c）的易位，caspase的激活和聚（ADP-核糖）聚合酶（PARP）的切割存在于JAK 2/STAT 3信号转导下调后的凋亡CRC细胞中。此外，JAK 2/STAT 3信号传导的抑制抑制了CRC异种移植肿瘤的生长。我们发现JAK 2/STAT 3靶基因在异种移植肿瘤中减少;同时caspase级联反应被激活。我们的研究结果阐明了JAK 2/STAT 3信号在CRC凋亡中的生物学意义，并提供了新的证据，即JAK 2/STAT 3的抑制通过线粒体凋亡途径诱导细胞凋亡。因此，JAK 2/STAT 3信号通路可能是CRC治疗的潜在靶点。
Abnormalities in the JAK2/STAT3 pathway are involved in the pathogenesis of colorectal cancer (CRC), including apoptosis. However, the exact mechanism by which dysregulated JAK2/STAT3 signalling contributes to the apoptosis has not been clarified. To investigate the role of both JAK2 and STAT3 in the mechanism underlying CRC apoptosis, we inhibited JAK2 with AG490 and depleted STAT3 with a small interfering RNA. Our data showed that inhibition of JAK2/STAT3 signalling induced CRC cellular apoptosis via modulating the Bcl‐2 gene family, promoting the loss of mitochondrial transmembrane potential (Δψm) and the increase of reactive oxygen species. In addition, our results demonstrated that the translocation of cytochrome c (Cyt c), caspase activation and cleavage of poly (ADP‐ribose) polymerase (PARP) were present in apoptotic CRC cells after down‐regulation of JAK2/STAT3 signalling. Moreover, inhibition of JAK2/STAT3 signalling suppressed CRC xenograft tumour growth. We found that JAK2/STAT3 target genes were decreased; meanwhile caspase cascade was activated in xenograft tumours. Our findings illustrated the biological significance of JAK2/STAT3 signalling in CRC apoptosis, and provided novel evidence that inhibition of JAK2/STAT3 induced apoptosis via the mitochondrial apoptotic pathway. Therefore, JAK2/STAT3 signalling may be a potential target for therapy of CRC.
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