CXCL12 chemokine expression and secretion regulates colorectal carcinoma cell anoikis through Bim-mediated intrinsic apoptosis.
CXCL12 chemokine expression and secretion regulates colorectal carcinoma cell anoikis through Bim-mediated intrinsic apoptosis.
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DOI：
10.1371/journal.pone.0012895
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发表时间：
2010-09-22
期刊：
影响因子：
3.7
通讯作者：
Dwinell MB
中科院分区：
文献类型：
--
作者：
Drury LJ;Wendt MK;Dwinell MB
对失巢凋亡的抗性，即由细胞粘附到底层细胞外基质的丧失引发的细胞凋亡，是转移性癌症的标志。以前，我们已经表明，结肠直肠癌细胞中CXCL 12表达的重建通过增强失巢凋亡敏感性来抑制转移。这些研究的目的是确定调节CXCL 12介导的失巢凋亡的信号传导机制。通过结晶紫染色、免疫荧光显微镜和免疫印迹分析检查的粘附表明，与由CXCL 12组成型模拟的细胞中的粘附损失相对应的粘着斑信号传导减少。百日咳毒素处理抑制了粘附的丧失，表明CXCL 12通过Gα i蛋白偶联受体调节失巢凋亡。通过碘化丙啶染色、半胱天冬酶活性测定和免疫印迹，与GFP对照细胞相比，表达CXCL 12的非粘附性HCT 116和HT 29结肠直肠癌细胞表现出增强的失巢凋亡敏感性。在poly-HEMA上培养的产生CXCL 12的癌显示出在细胞色素c释放和半胱天冬酶-9活化之前升高的Bim和Mcl-1和Bcl-2的损失。RNAi敲除Bim逆转了表达CXCL 12的细胞的失巢凋亡敏感性，并在原位转移小鼠模型中促进了软琼脂病灶形成和肝肿瘤的增加。这些数据表明CXCL 12通过激活Bim介导的内在凋亡途径增加失巢凋亡而提供转移屏障。这些结果强调了保持CXCL 12表达对结肠直肠癌对失巢凋亡敏感和最小化肿瘤进展的重要性。
Resistance to anoikis, apoptosis triggered by a loss of cellular adhesion to the underlying extracellular matrix, is a hallmark of metastatic cancer. Previously we have shown re-establishment of CXCL12 expression in colorectal carcinoma cells inhibits metastasis by enhancing anoikis sensitivity. The objective of these studies was to define the signaling mechanisms regulating CXCL12-mediated anoikis. Adhesion, examined by crystal violet staining, immunofluorescence microscopy, and immunoblot analysis indicated decreased focal adhesion signaling corresponding with loss of adhesion in cells constitutively simulated by CXCL12. Loss of adhesion was inhibited by pertussis toxin treatment, indicating CXCL12 regulating anoikis through Gαi-protein coupled receptors. Non-adherent HCT116 and HT29 colorectal carcinoma cells expressing CXCL12 exhibited enhanced anoikis sensitivity by propidium iodide staining, caspase activity assays, and immunoblot compared to GFP control cells. CXCL12 producing carcinomas cultured on poly-HEMA displayed heightened Bim and loss of Mcl-1 and Bcl-2 preceding cytochrome c release, and caspase-9 activation. RNAi knockdown of Bim reversed anoikis sensitivity of CXCL12-expressing cells and fostered increased soft-agar foci formation and hepatic tumors in an orthotopic mouse model of metastasis. These data indicate CXCL12 provides a barrier to metastasis by increasing anoikis via activation of a Bim-mediated intrinsic apoptotic pathway. These results underscore the importance of retaining CXCL12 expression to sensitize colorectal carcinomas to anoikis and minimize tumor progression.
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新型的CXCL12GAMMA同工型编码一个非结构化的阳离子结构域，该结构域调节了与糖胺聚糖和CXCR4的生物活性和相互作用。
影响因子：
3.7
作者：
Laguri, Cedric;Sadir, Rabia;Rueda, Patricia;Baleux, Francoise;Gans, Pierre;Arenzana-Seisdedos, Fernando;Lortat-Jacob, Hugues
通讯作者：
Lortat-Jacob, Hugues
影响因子：
8
作者：
Marani, M;Hancock, D;Lemoine, NR
通讯作者：
Lemoine, NR
影响因子：
3.8
作者：
Cao, Yanna;Deng, Chunyan;Ko, Tien C.
通讯作者：
Ko, Tien C.
影响因子：
64.8
作者：
Müller, A;Homey, B;Zlotnik, A
通讯作者：
Zlotnik, A
DOI：
10.1083/jcb.124.4.619
发表时间：
1994-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Frisch SM;Francis H
通讯作者：
Francis H