Inhibition of BMP and of TGFβ receptors downregulates expression of XIAP and TAK1 leading to lung cancer cell death.
Inhibition of BMP and of TGFβ receptors downregulates expression of XIAP and TAK1 leading to lung cancer cell death.
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DOI：
10.1186/s12943-016-0511-9
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发表时间：
2016-04-06
期刊：
影响因子：
37.3
通讯作者：
Langenfeld J
中科院分区：
文献类型：
--
作者：
Augeri DJ;Langenfeld E;Castle M;Gilleran JA;Langenfeld J
骨形态发生蛋白（BMP）是转化生长因子（TGFβ）超家族的一部分，在许多肿瘤中异常表达。用小分子抑制剂抑制BMP受体会降低肺癌细胞的生长并诱导其死亡，这涉及通过Smad依赖性机制下调Id 1和Id 3。在发育过程中，BMP和TGFβ信号转导利用Smad-1/5独立机制来稳定X连锁凋亡抑制蛋白（XIAP）的表达并激活TGFβ激活激酶1（TAK 1），这是已知的凋亡的有效抑制剂。BMP信号传导在调节癌细胞中XIAP和TEK 1中的作用尚不清楚。此外，尚未阐明BMP和TGFβ信号级联在调节癌细胞中TAK 1活化中的相互作用。利用靶向BMP I型受体的siRNA和抑制剂、BMP和TGFβ I型受体的抑制剂以及BMP和TGF β I型和II型受体的抑制剂，在肺癌细胞中检查BMP和TGFβ信号传导通路之间的反馈调节以及它们对XIAP、TAK 1和Id 1的调节。我们发现，在肺癌细胞中抑制BMP信号传导后，TGFβ信号级联被激活。BMP和TGFβ途径都激活了TAK 1，然后增加了Id 1的表达。抑制TGFβ信号传导增加了Id 1的表达，但当BMP信号传导受到抑制时除外，这随后导致Id 1表达的剂量相关性降低。BMP和TGFβ信号传导的抑制增强了TAK 1的下调。我们的数据还表明，BMP II型受体的阻断增强了XIAP的下调，这在降低TAK 1的活性中是重要的。敲除研究表明，XIAP和TAK 1都调节肺癌细胞的存活。这篇论文强调了靶向BMP和TGFβ I型和II型受体导致XIAP、TAK 1和Id 1下调，从而导致肺癌细胞的细胞死亡。靶向BMP和TGFβ受体的小分子抑制剂代表了治疗癌症患者的潜在新手段。本文的在线版本（doi：10.1186/s12943-016-0511-9）包含补充材料，可供授权用户使用。
Bone morphogenetic proteins (BMP) are embryonic proteins that are part of the transforming growth factor (TGFβ) superfamily, which are aberrantly expressed in many carcinomas. Inhibition of BMP receptors with small molecule inhibitors decreases growth and induces death of lung cancer cells, which involves the downregulation of Id1 and Id3 by a Smad dependent mechanism. Developmentally, BMP and TGFβ signaling utilizes Smad-1/5 independent mechanisms to stabilize the expression of X-linked inhibitor of apoptosis protein (XIAP) and activate TGFβ activated kinase 1 (TAK1), which are known to be potent inhibitors of apoptosis. The role of BMP signaling in regulating XIAP and TAK1 in cancer cells is poorly understood. Furthermore, the interaction between the BMP and TGFβ signaling cascades in regulating the activation of TAK1 in cancer cells has not been elucidated. Feedback regulation between the BMP and TGFβ signaling pathways and their regulation of XIAP, TAK1, and Id1 were examined in lung cancer cells utilizing siRNA and inhibitors targeting BMP type I receptors, inhibitors of BMP and TGFβ type I receptors, and an inhibitor of BMP and TGFβ type I and type II receptors. We show that upon inhibition of BMP signaling in lung cancer cells, the TGFβ signaling cascade is activated. Both the BMP and TGFβ pathways activate TAK1, which then increases the expression of Id1. Inhibition of TGFβ signaling increased Id1 expression except when BMP signaling is suppressed, which then causes a dose-related decrease in the expression of Id1. Inhibition of both BMP and TGFβ signaling enhances the downregulation of TAK1. Our data also suggests that the blockade of the BMP type II receptor enhances the downregulation XIAP, which is important in decreasing the activity of TAK1. Knockdown studies demonstrate that both XIAP and TAK1 regulate the survival of lung cancer cells. This paper highlights that targeting the BMP and TGFβ type I and type II receptors causes a downregulation of XIAP, TAK1, and Id1 leading to cell death of lung cancer cells. Small molecule inhibitors targeting the BMP and TGFβ receptors represents a potential novel means to treat cancer patients. The online version of this article (doi:10.1186/s12943-016-0511-9) contains supplementary material, which is available to authorized users.