Targeted Blockade of JAK/STAT3 Signaling Inhibits Ovarian Carcinoma Growth.
Targeted Blockade of JAK/STAT3 Signaling Inhibits Ovarian Carcinoma Growth.
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针对JAK/STAT3信号传导的靶向封锁抑制了卵巢癌的生长。
DOI：
10.1158/1535-7163.mct-14-0800
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发表时间：
2015-04
影响因子：
5.7
通讯作者：
Connolly DC
中科院分区：
文献类型：
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作者：
Gritsina G;Xiao F;O'Brien SW;Gabbasov R;Maglaty MA;Xu RH;Thapa RJ;Zhou Y;Nicolas E;Litwin S;Balachandran S;Sigal LJ;Huszar D;Connolly DC
卵巢癌（OC）是美国女性死亡的第五大原因。信号转导子和转录激活子3（STAT 3）的持续激活在OC中经常被检测到。STAT 3通过细胞因子受体、生长因子受体和非生长因子受体酪氨酸激酶被Janus家族激酶（JAK）激活。STAT 3的激活介导肿瘤细胞增殖、存活、运动、侵袭和血管生成，并且最近的工作表明STAT 3激活抑制抗肿瘤免疫应答并支持肿瘤促进性炎症。我们假设JAK/STAT 3通路的治疗靶向将通过直接作用于OC细胞和抑制肿瘤微环境（TME）中的细胞来抑制肿瘤生长。为了测试这一点，我们评估了小分子JAK抑制剂AZD 1480对体外OC细胞的细胞活力、凋亡、增殖、迁移和粘附的影响。然后，我们在OC转基因小鼠模型中评估了AZD 1480对体内肿瘤生长和进展、基因表达、肿瘤相关基质金属蛋白酶（MMP）活性和免疫细胞群的影响。AZD 1480处理抑制STAT 3磷酸化和DNA结合，以及培养的OC细胞的迁移和粘附，以及小鼠卵巢肿瘤的生长速度、体积和腹水产生。此外，药物治疗导致基因表达改变，肿瘤相关MMP活性降低，荷瘤小鼠腹膜肿瘤微环境中的抑制性T细胞比对照小鼠少。综上所述，我们的研究结果表明，JAK 2/STAT 3通路的药理学抑制导致卵巢肿瘤生长和进展所必需的功能中断，代表了一种有前途的治疗策略。
Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy.