Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma.
Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma.
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DOI：
10.1158/0008-5472.can-12-2353
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发表时间：
2013-07-01
期刊：
影响因子：
11.2
通讯作者：
DeClerck YA
中科院分区：
文献类型：
--
作者：
Ara T;Nakata R;Sheard MA;Shimada H;Buettner R;Groshen SG;Ji L;Yu H;Jove R;Seeger RC;DeClerck YA
耐药性是癌症治疗失败的主要原因。在这里，我们评估了STAT 3在人类神经母细胞瘤环境介导的耐药（EMDR）中的作用。我们确定STAT 3在大多数神经母细胞瘤细胞系中不具有组成性活性，但在单独用白细胞介素-6（IL-6）和与可溶性IL-6受体（sIL-6 R）联合治疗后迅速活化。用IL-6处理神经母细胞瘤细胞以STAT 3依赖性方式保护它们免于药物诱导的凋亡，因为IL-6的保护作用在STAT 3抑制剂存在下和在STAT 3敲低后被废除。当细胞暴露于IL-6时，STAT 3对于几种存活因子如生存素（BIRC 5）和Bcl-xL（BCL 2L 1）的上调是必需的。更重要的是，IL-6介导的STAT 3激活被人单核细胞产生的sIL-6 R增强，这表明单核细胞在促进IL-6介导的EMDR中具有重要功能。我们的数据还指出肿瘤细胞和骨髓基质细胞之间存在STAT 3的相互激活，骨髓基质细胞不仅包括单核细胞，还包括Treg细胞和非骨髓基质细胞。因此，这些数据确定了神经母细胞瘤细胞与其微环境之间的IL-6/sIL-6 R/STAT 3相互作用途径，该途径有助于耐药性。
Drug resistance is a major cause of treatment failure in cancer. Here we have evaluated the role of STAT3 in environment-mediated drug resistance (EMDR) in human neuroblastoma. We determined that STAT3 was not constitutively active in most neuroblastoma cell lines but was rapidly activated upon treatment with interleukin-6 (IL-6) alone and in combination with the soluble IL-6 receptor (sIL-6R). Treatment of neuroblastoma cells with IL-6 protected them from drug-induced apoptosis in a STAT3-dependent manner because the protective effect of IL-6 was abrogated in the presence of a STAT3 inhibitor and upon STAT3 knockdown. STAT3 was necessary for the upregulation of several survival factors such as survivin (BIRC5) and Bcl-xL (BCL2L1) when cells were exposed to IL-6. Importantly, IL-6-mediated STAT3 activation was enhanced by sIL-6R produced by human monocytes, pointing to an important function of monocytes in promoting IL-6-mediated EMDR. Our data also point to the presence of reciprocal activation of STAT3 between tumor cells and bone marrow stromal cells including not only monocytes but also Treg cells and non-myeloid stromal cells. Thus, the data identify an IL-6/sIL-6R/STAT3 interactive pathway between neuroblastoma cells and their microenvironment that contributes to drug resistance.