Neuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer
Neuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer
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DOI：
10.1158/0008-5472.can-07-0858
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发表时间：
2007-11-01
期刊：
影响因子：
11.2
通讯作者：
Sood, Anil K.
中科院分区：
文献类型：
--
作者：
Landen, Charles N., Jr.;Lin, Yvonne G.;Sood, Anil K.
越来越多的证据表明，慢性压力和其他行为条件与癌症的发病机制和进展有关，但这种关联所涉及的机制知之甚少。我们研究了两种应激介质，去甲肾上腺素和肾上腺素，对信号转导和转录激活因子3（STAT 3）的激活的影响，STAT 3是一种转录因子，有助于许多促癌途径。将卵巢癌细胞系暴露于增加浓度的去甲肾上腺素或肾上腺素显示，两者都以剂量依赖性方式独立地增加磷酸化STAT 3的水平。核提取物的免疫定位和ELISA证实了响应于去甲肾上腺素的核STAT 3增加。用普萘洛尔阻断β 1-和β 2-肾上腺素能受体，用KT 5720阻断蛋白激酶A，但用α受体阻断剂哌唑嗪（α 1）和/或育亨宾（α 2）不能抑制STAT 3的激活。用抗白细胞介素6（IL-6）抗体或小干扰RNA（siRNA）介导的IL-6或gp 130减少预处理不抑制儿茶酚胺介导的STAT 3激活。关于STAT 3激活的影响，暴露于去甲肾上腺素导致侵袭和基质金属蛋白酶（MMP-2和MMP-9）的产生增加。这些作用被靶向STAT 3的siRNA完全阻断。在小鼠中，用脂质体掺入的针对STAT 3的siRNA治疗显著降低了异丙肾上腺素刺激的肿瘤生长。这些研究表明，去甲肾上腺素和肾上腺素通过β 1/β 2-肾上腺素能受体和蛋白激酶A对STAT 3的IL-6非依赖性活化，导致基质金属蛋白酶产生、侵袭和体内肿瘤生长增加，这可以通过下调STAT 3来改善。
There is growing evidence that chronic stress and other behavioral conditions are associated with cancer pathogenesis and progression, but the mechanisms involved in this association are poorly understood. We examined the effects of two mediators of stress, norepinephrine and epinephrine, on the activation of signal transducer and activator of transcription-3 (STAT3), a transcription factor that contributes to many promalignant pathways. Exposure of ovarian cancer cell lines to increasing concentrations of norepinephrine or epinephrine showed that both independently increased levels of phosphorylated STAT3 in a dose-dependent fashion. Immunolocalization and ELISA of nuclear extracts confirmed increased nuclear STAT3 in response to norepinephrine. Activation of STAT3 was inhibited by blockade of the beta 1- and beta 2-adrenergic receptors with propranolol, and by blocking protein kinase A with KT5720, but not with the alpha receptor blockers prazosin (alpha 1) and/or yohimbine (alpha 2). Catecholamine-mediated STAT3 activation was not inhibited by pretreatment with an anti-interleukin 6 (IL-6) antibody or with small interfering RNA (siRNA)-mediated decrease in IL-6 or gp130. Regarding the effects of STAT3 activation, exposure to norepinephrine resulted in an increase in invasion and matrix metalloproteinase (MMP-2 and MMP-9) production. These effects were completely blocked by STAT3-targeting siRNA. In mice, treatment with liposome-incorporated siRNA directed against STAT3 significantly reduced isoproterenol-stimulated tumor growth. These studies show IL-6-independent activation of STAT3 by norepinephrine and epinephrine, proceeding through the beta 1/beta 2-adrenergic receptors and protein kinase A, resulting in increased matrix metalloproteinase production, invasion, and in vivo tumor growth, which can be ameliorated by the down-regulation of STAT3.