Acidosis promotes invasiveness of breast cancer cells through ROS-AKT-NF-κB pathway.
Acidosis promotes invasiveness of breast cancer cells through ROS-AKT-NF-κB pathway.
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DOI：
10.18632/oncotarget.2514
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发表时间：
2014-12-15
期刊：
影响因子：
--
通讯作者：
Mo YY
中科院分区：
文献类型：
--
作者：
Gupta SC;Singh R;Pochampally R;Watabe K;Mo YY
众所周知，酸性微环境促进肿瘤的发生，然而，其潜在的机制在很大程度上仍然未知。在目前的研究中，我们表明，酸中毒促进乳腺癌细胞的侵袭性，通过一系列的信号事件。首先，我们的研究表明NF-κB是酸中毒诱导细胞侵袭的关键因素。酸中毒激活NF-κB而不影响STAT 3活性; NF-κB p65的敲低消除了酸中毒诱导的侵袭活性。接下来，我们发现NF-κB的激活是通过IκBα的磷酸化和降解以及p65的磷酸化和核转位介导的。在NF-κB信号传导的上游，AKT在酸性条件下被激活。此外，酸中毒会诱导活性氧簇（ROS）的产生，而活性氧簇（ROS）清除剂可以抑制活性氧簇（ROS）的产生，从而逆转酸中毒诱导的AKT和NF-κB的激活以及侵袭性。作为AKT的负调节因子，PTEN被酸中毒诱导的ROS氧化和失活。最后，抑制NADPH氧化酶（NOX）抑制酸中毒诱导的ROS的产生，表明NOX参与酸中毒诱导的信号级联反应。值得关注的是，酸中毒诱导的ROS产生和AKT和NF-κB的活化仅在癌细胞中检测到，而在非恶性细胞中检测不到。总之，这些结果证明了乳腺癌细胞中癌症特异性酸中毒诱导的信号级联，导致细胞侵袭。
It is well known that acidic microenvironment promotes tumorigenesis, however, the underlying mechanism remains largely unknown. In the present study, we show that acidosis promotes invasiveness of breast cancer cells through a series of signaling events. First, our study indicates that NF-κB is a key factor for acidosis-induced cell invasion. Acidosis activates NF-κB without affecting STAT3 activity; knockdown of NF-κB p65 abrogates the acidosis-induced invasion activity. Next, we show that the activation of NF-κB is mediated through phosphorylation and degradation of IκBα; and phosphorylation and nuclear translocation of p65. Upstream to NF-κB signaling, AKT is activated under acidic conditions. Moreover, acidosis induces generation of reactive oxygen species (ROS) which can be suppressed by ROS scavengers, reversing the acidosis-induced activation of AKT and NF-κB, and invasiveness. As a negative regulator of AKT, PTEN is oxidized and inactivated by the acidosis-induced ROS. Finally, inhibition of NADPH oxidase (NOX) suppresses acidosis-induced ROS production, suggesting involvement of NOX in acidosis-induced signaling cascade. Of considerable interest, acidosis-induced ROS production and activation of AKT and NF-κB can be only detected in cancer cells, but not in non-malignant cells. Together, these results demonstrate a cancer specific acidosis-induced signaling cascade in breast cancer cells, leading to cell invasion.
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影响因子：
8
作者：
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肿瘤微环境产生的酸度驱动局部侵袭。
影响因子：
11.2
作者：
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通讯作者：
Gillies RJ