Inhibition of IL-6/STAT3 signaling in human cancer cells using Evista
Inhibition of IL-6/STAT3 signaling in human cancer cells using Evista
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使用 Evista 抑制人类癌细胞中的 IL-6/STAT3 信号传导
DOI：
10.1016/j.bbrc.2017.07.067
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发表时间：
2017-09-09
影响因子：
3.1
通讯作者：
Lin, Li
中科院分区：
文献类型：
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作者：
Shi, Wei;Yan, Dan;Lin, Li
IL-6/STAT 3信号通路的持续激活在包括乳腺癌、结肠癌和多发性骨髓瘤在内的人类癌症中经常被检测到。IL-6/STAT 3有望成为肿瘤防治的新靶点。然而，目前临床上可用于癌症治疗的高效、特异性和安全性的STAT 3抑制剂很少。Evista（盐酸雷洛昔芬）是一种选择性雌激素受体调节剂，已被用于预防和治疗骨质疏松症，并被批准用于降低浸润性乳腺癌的风险。我们先前的研究发现雷洛昔芬抑制IL-6/GP 130相互作用，导致STAT 3磷酸化的阻断。在我们目前的研究中，我们研究了Evista对IL-6/GP 130/STAT 3信号通路和癌细胞活力的影响。我们首先证明Evista抑制了乳腺癌细胞系MDB-MB-231、结肠癌细胞系HCT 116和多发性骨髓瘤癌细胞系U266中STAT 3的组成性激活。Evista还可抑制MCF-7、HT 29和MM. 1 S癌细胞系中IL-6诱导的STAT 3磷酸化。凋亡诱导在MDA-MB-231、HCT 116和U266中发挥作用，如通过增加的半胱天冬酶-3切割所证明的。然而，Evista并不抑制由IFN-α、IFN-γ和IL-4引起的STAT 1、STAT 2、STAT 4或STAT 6磷酸化，也不抑制由MCF-7细胞系中的LIF诱导的STAT 3磷酸化。Evista减弱了STAT 3磷酸化，降低了STAT 3的转录活性，但对pGL 3和AP 1转录荧光素酶活性的影响要小得多，并降低了体外细胞活力。这些结果表明，Evista有可能通过靶向IL-6/STAT 3信号传导而成为乳腺癌和其他癌症如结肠癌或多发性骨髓瘤的化学预防剂。(C)2017爱思唯尔公司All rights reserved.
Persistent activation of IL-6/STAT3 signaling pathway has been frequently detected in human cancer including breast cancer, colon cancer and multiple myeloma. IL-6/STAT3 can be a promising target for cancer prevent and treatment. However, few STAT3 inhibitors with high efficiency, specificity and safety is available for present clinical cancer therapy. Evista (Raloxifene-HCI) is known as selective estrogen receptor modulator which has been used for the prevention and treatment of osteoporosis and was approved for reducing the risk of invasive breast cancer. Our previous study found that Raloxifene inhibited IL-6/GP130 interaction, resulting in blockade of STAT3 phosphorylation. In our present study, we examined the effect on IL-6/GP130/STAT3 signaling pathway and cancer cell viability with Evista. We first demonstrated Evista inhibited constitutive activation of STAT3 in breast cancer cell line MDB-MB-231, colon cancer cell line HCT116 and multiple myeloma cancer cell line U266. Evista also inhibited phosphorylation of STAT3 induced by IL-6 in MCF-7, HT29 and MM.1S cancer cell lines. Induction of apoptosis was exerted in MDA-MB-231, HCT116 and U266 as evidenced by increased caspase-3 cleavage. However, Evista did not inhibit STAT1, STAT2, STAT4 or STAT6 phosphorylation elicited by IFN-alpha, IFN-gamma and IL-4, nor phosphorylation of STAT3 induced by LIF in MCF-7 cell lines. Evista attenuated STAT3 phosphorylation, decreased STAT3 transcriptional activity but much less in pGL3 and AP1 transcriptional luciferase activity, and decreased cell viability in vitro. These results suggest that it may be possible for Evista to emerge as a chemoprevention agent for breast cancer and other cancers such as colon cancer or multiple myeoloma by targeting IL-6/STAT3 signaling. (C) 2017 Elsevier Inc. All rights reserved.