Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2-reactive oxygen species-linked signaling pathway
Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2-reactive oxygen species-linked signaling pathway
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DOI：
10.1093/carcin/bgp203
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发表时间：
2010-04-01
期刊：
影响因子：
4.7
通讯作者：
Kim, Jae-Hong
中科院分区：
文献类型：
--
作者：
Choi, Jung-A;Lee, Jin-Wook;Kim, Jae-Hong
白三烯B-4 （LTB4）是一种炎症介质，在许多炎症疾病的发病机制中具有强大的生物活性。在本研究中，我们发现乳腺癌细胞中低亲和力LTB4受体BLT2的表达显著上调。此外，我们观察到BLT2通过特异性拮抗剂LY255283或通过siBLT2 RNA干扰抑制可导致乳腺癌细胞中显著的凋亡细胞死亡，特别是雌激素受体（ER）阴性的MDA-MB-468和MDA-MB-453细胞，这表明BLT2在这些乳腺癌细胞的存活中起作用。为了了解BLT2介导潜在促生存信号的下游机制，我们发现活性氧（ROS）的产生升高与BLT2介导的生存有关。NADPH氧化酶家族成员Nox1的表达在这些乳腺癌细胞中也以BLT2依赖的方式高度上调，这表明“Nox1衍生的ROS”位于BLT2的下游。与“Nox1-ROS”在促生存信号传导中的作用一致，用siNox1敲低Nox1或用ROS清除剂治疗会导致这些乳腺癌细胞发生明显的凋亡死亡。综上所述，我们的研究结果首次证明，“BLT2-Nox1-ROS”连锁级联参与促生存信号传导，特别是在er阴性乳腺癌细胞中。
Leukotriene B-4 (LTB4) is an inflammatory mediator with potent biological activities in the pathogenesis of many inflammatory diseases. In the present study, we found that expression of BLT2, a low-affinity LTB4 receptor, is significantly upregulated in breast cancer cells. In addition, we observed that inhibition of BLT2 by a specific antagonist, LY255283, or by siBLT2 RNA interference caused dramatic apoptotic cell death in breast cancer cells, especially in the estrogen receptor (ER)-negative MDA-MB-468 and MDA-MB-453 cells, suggesting a role for BLT2 in survival of these breast cancer cells. In an approach to understand the downstream mechanism by which BLT2 mediates the potential pro-survival signaling, we found that the elevated reactive oxygen species (ROS) generation is associated with BLT2-mediated survival. Expression of Nox1, a member of the NADPH oxidase family, is also highly upregulated in a BLT2-dependent manner in these breast cancer cells, suggesting that 'Nox1-derived ROS' lie downstream of BLT2. Consistent with the proposed role of 'Nox1-ROS' in pro-survival signaling, knockdown of Nox1 with siNox1 or treatment with a ROS scavenging agent caused dramatic apoptotic death in these breast cancer cells. Taken together, our results demonstrate, for the first time, that the 'BLT2-Nox1-ROS'-linked cascade is involved in the pro-survival signaling, especially in ER-negative breast cancer cells.