Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways
Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways
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DOI：
10.1073/pnas.1101133108
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发表时间：
2011-10-25
影响因子：
11.1
通讯作者：
Dwinell, Michael B.
中科院分区：
文献类型：
--
作者：
Drury, Luke J.;Ziarek, Joshua J.;Dwinell, Michael B.
趋化因子和趋化因子受体广泛参与癌症转移。以前，我们证明了趋化因子CXCL 12的表观遗传沉默使乳腺癌和结肠癌细胞对内分泌信号和远处组织转移敏感。然而，肿瘤细胞产生CXCL 12调节播散的确切机制仍不清楚。在这里，我们表明，CXCL 12的管理，通过有效地限制结肠直肠癌或小鼠黑色素瘤的转移，延长荷瘤小鼠的生存期。因为分泌的CXCL 12是单体和二聚体物质的平衡混合物，所以使用促进（单体）或停止（二聚体）趋化性的寡聚体变体来剖析中断癌转移的机制。单体CXCL 12动员细胞内钙，抑制cAMP信号传导，募集β-arrestin-2，并刺激粘附性肌动蛋白积累和细胞迁移。二聚体CXCL 1/2激活G蛋白依赖的钙流，腺苷酸环化酶抑制，和ERK 1/2的快速激活，但只有微弱的，如果有的话，招募抑制蛋白，刺激肌动蛋白聚合，或促进趋化性。NMR分析表明，CXCL 12单体与CXCR 4进行了特异性接触，这些接触在二聚化后丢失。我们的结果建立了通过施用CXCL 12抑制CXCR 4介导的转移的潜力。趋化因子介导的迁移和β-抑制蛋白反应并不决定CXCL 12的抗肿瘤作用。我们的结论是，细胞迁移是严格调节的选择性CXCR 4信号诱发独特的相互作用与不同的配体四级结构。
Chemokines and chemokine receptors are extensively and broadly involved in cancer metastasis. Previously, we demonstrated that epigenetic silencing of the chemokine CXCL12 sensitizes breast and colon cancer cells to endocrine signaling and metastasis to distant tissues. Yet, the precise mechanism whereby CXCL12 production by tumor cells regulates dissemination remains unclear. Here, we show that administration of CXCL12 extended survival of tumor-bearing mice by potently limiting metastasis of colorectal carcinoma or murine melanoma. Because secreted CXCL12 is a mixture of monomeric and dimeric species in equilibrium, oligomeric variants that either promote (monomer) or halt (dimer) chemotaxis were used to dissect the mechanisms interrupting carcinoma metastasis. Monomeric CXCL12 mobilized intracellular calcium, inhibited cAMP signaling, recruited beta-arrestin-2, and stimulated filamentous-actin accumulation and cell migration. Dimeric CXCL12 activated G-protein-dependent calcium flux, adenylyl cyclase inhibition, and the rapid activation of ERK1/2, but only weakly, if at all, recruited arrestin, stimulated actin polymerization, or promoted chemotaxis. NMR analyses illustrated that CXCL12 monomers made specific contacts with CXCR4 that were lost following dimerization. Our results establish the potential for inhibiting CXCR4-mediated metastasis by administration of CXCL12. Chemokine-mediated migration and beta-arrestin responses did not dictate the antitumor effect of CXCL12. We conclude that cellular migration is tightly regulated by selective CXCR4 signaling evoked by unique interactions with distinct ligand quaternary structures.