A Novel CXCR3-B Chemokine Receptor-induced Growth-inhibitory Signal in Cancer Cells Is Mediated through the Regulation of Bach-1 Protein and Nrf2 Protein Nuclear Translocation
A Novel CXCR3-B Chemokine Receptor-induced Growth-inhibitory Signal in Cancer Cells Is Mediated through the Regulation of Bach-1 Protein and Nrf2 Protein Nuclear Translocation
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DOI：
10.1074/jbc.m113.508044
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发表时间：
2014-02-07
影响因子：
4.8
通讯作者：
Pal, Soumitro
中科院分区：
文献类型：
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作者：
Balan, Murugabaskar;Pal, Soumitro
背景：趋化因子受体CXCR3-B启动抑制信号。结果：CXCR3-B介导的信号可诱导乳腺癌细胞凋亡，抑制自噬。它与BACH-1的核转位、NRF2的核输出和HO-1的下调有关。结论：CXCR3-B介导的信号可促进乳腺癌细胞的凋亡。意义：诱导CXCR3-B介导的信号转导可作为乳腺癌治疗的一种新的治疗方法。趋化因子及其受体在调节肿瘤生长和进展中发挥不同的作用。受体CXCR3可以有两个功能相反的剪接变异体。CXCR3-A促进细胞生长，而CXCR3-B介导生长抑制信号。然而，通过CXCR3-B在癌细胞中传递的负信号还没有得到很好的表征。在本研究中，我们发现CXCR3-B介导的信号在MCF-7和T47D乳腺癌细胞中诱导细胞凋亡。CXCR3-B信号通路可降低抗凋亡蛋白Bcl2和Bclxl的表达，增加细胞凋亡裂解聚(ADP-核糖)聚合酶的表达。随着细胞凋亡的上调，CXCR3-B信号与细胞自噬的减少以及自噬标记物Beclin-1和LC3B水平的降低有关。值得注意的是，CXCR3-B在转录水平下调了细胞保护和抗凋亡分子血红素加氧酶-1(HO-1)的表达。与HO-1表达相关的重要转录因子Bach-1的核定位增加，Nrf2的核输出增加。我们还观察到CXCR3-B促进p38MAPK的激活和ERK-1/2的抑制。当我们抑制p38活性或抑制Bach-1时，CXCR3-B不能在最佳水平诱导癌细胞凋亡。此外，当我们过表达HO-1时，CXCR3-B诱导的细胞凋亡被下调。总之，我们的数据表明，CXCR3-B通过调节Bach-1和Nrf2的核转位以及下调HO-1的表达，在乳腺癌细胞中介导了一种生长抑制信号。我们认为，诱导CXCR3-B介导的信号转导可以作为一种新的治疗方法，其目的是促进肿瘤细胞的凋亡。
Background: The chemokine receptor CXCR3-B initiates inhibitory signals. Results: CXCR3-B-mediated signal induced apoptosis and inhibited autophagy of breast cancer cells. It is associated with nuclear translocation of Bach-1, nuclear export of Nrf2, and down-regulation of HO-1. Conclusion: A CXCR3-B-mediated signal promotes apoptosis of breast cancer cells. Significance: Induction of CXCR3-B-mediated signaling can serve as a novel therapeutic approach for the treatment of breast cancer.Chemokines and their receptors play diverse roles in regulating cancer growth and progression. The receptor CXCR3 can have two splice variants with opposite functions. CXCR3-A promotes cell growth, whereas CXCR3-B mediates growth-inhibitory signals. However, the negative signals through CXCR3-B in cancer cells are not well characterized. In this study, we found that CXCR3-B-mediated signaling in MCF-7 and T47D breast cancer cells induced apoptotic cell death. Signals through CXCR3-B decreased the levels of the antiapoptotic proteins Bcl-2 and Bcl-xL and increased the expression of apoptotic cleaved poly(ADP-ribose) polymerase. Along with up-regulation in apoptosis, CXCR3-B signals were associated with a decrease in cellular autophagy with reduced levels of the autophagic markers Beclin-1 and LC3B. Notably, CXCR3-B down-regulated the expression of the cytoprotective and antiapoptotic molecule heme oxygenase-1 (HO-1) at the transcriptional level. There was an increased nuclear localization of Bach-1 and nuclear export of Nrf2, which are important negative and positive transcription factors, respectively, for HO-1 expression. We also observed that CXCR3-B promoted the activation of p38 MAPK and the inhibition of ERK-1/2. CXCR3-B could not induce cancer cell apoptosis at the optimal level when we either inhibited p38 activity or knocked down Bach-1. Further, CXCR3-B-induced apoptosis was down-regulated when we overexpressed HO-1. Together, our data suggest that CXCR3-B mediates a growth-inhibitory signal in breast cancer cells through the modulations of nuclear translocation of Bach-1 and Nrf2 and down-regulation of HO-1. We suggest that the induction of CXCR3-B-mediated signaling can serve as a novel therapeutic approach where the goal is to promote tumor cell apoptosis.