Regulation of Janus-activated kinase-2 (JAK2) by diindolylmethane in ovarian cancer in vitro and in vivo
Regulation of Janus-activated kinase-2 (JAK2) by diindolylmethane in ovarian cancer in vitro and in vivo
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DOI：
10.5582/ddt.2012.v6.2.94
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发表时间：
2012-04-01
影响因子：
3.1
通讯作者：
Srivastava, Sanjay K.
中科院分区：
文献类型：
--
作者：
Kandala, Prabodh K.;Srivastava, Sanjay K.
Janus-activated kinase-2（JAK 2）在信号转导和转录激活因子3（STAT 3）的激活中起重要作用，在大多数卵巢肿瘤中过表达。我们以前曾报道过二吲哚甲烷（DIM）通过抑制STAT 3诱导卵巢癌细胞凋亡。然而，JAK 2在我们的模型中的作用尚未被理解，因此在本报告中进行了评估。以SKOV-3人卵巢癌细胞为研究对象，采用IL-3和EGF激活JAK 2，观察DIM对卵巢癌细胞增殖的影响。肿瘤异种移植研究用于确定体内JAK 2的调节。DIM处理以浓度依赖性方式阻断JAK 2在Tyr-1007处的磷酸化。在时间依赖性研究中，DIM对JAK 2的抑制早在1 h，随后是对STAT 3和Survivin的抑制。IL-3诱导的JAK 2和STAT 3的磷酸化被DIM显著阻断。IL-3处理阻断DIM诱导的细胞凋亡。EGF处理导致JAK 2和STAT 3的激活，但被DIM抑制。这些结果表明细胞因子和生长因子参与JAK 2/STAT 3的激活，DIM抑制它们的激活。此外，与单独顺铂相比，DIM与顺铂组合显著降低JAK 2的磷酸化。与对照相比，来自DIM处理的小鼠的肿瘤的蛋白质印迹分析显示JAK 2活化的显著抑制。这些发现为DIM单独或与卵巢癌化疗联合应用的进一步临床研究提供了依据。
Janus-activated kinase-2 (JAK2) plays an important role in the activation of signal transducer and activation of transcription 3 (STAT3), which is over expressed in majority of ovarian tumors. We have reported previously that diindolylmethane ( DIM) induces apoptosis in ovarian cancer cells by inhibiting STAT3. However, the role of JAK2 in our model was not yet understood and hence evaluated in this report. SKOV-3 human ovarian cancer cells were used to evaluate concentration and time dependent effects of DIM. Interleukin 3 (IL-3) and epidermal growth factor (EGF) were used to activate JAK2. Tumor xenograft studies were used to determine modulation of JAK2 in vivo. DIM treatment blocked the phosphorylation of JAK2 at Tyr-1007 in a concentration-dependent manner. In a time-dependent study, inhibition of JAK2 by DIM was as early as 1 h, which was followed by the inhibition of STAT3 and survivin. IL-3-induced phosphorylation of JAK2 and STAT3 was significantly blocked by DIM. IL-3 treatment blocked DIM-induced apoptosis. EGF treatment resulted in the activation of JAK2 and STAT3 but suppressed by DIM. These results indicate the involvement of cytokines and growth factors in the activation of JAK2/STAT3 and that DIM suppress their activation. Furthermore, DIM in combination with cisplatin drastically reduced the phosphorylation of JAK2 when compared to cisplatin alone. Western blot analysis of tumors from DIM treated mice showed significant inhibition of JAK2 activation as compared with controls. These findings provide a rationale for further clinical investigation of DIM for its potential use alone or in combination with chemotherapy of ovarian cancer.