CXCR4和CXCR7在人肾癌细胞中通过mTOR进行信号转导。

CXCR4 and CXCR7 transduce through mTOR in human renal cancer cells.

作者信息

Ieranò C, Santagata S, Napolitano M, Guardia F, Grimaldi A, Antignani E, Botti G, Consales C, Riccio A, Nanayakkara M, Barone M V, Caraglia M, Scala S

机构信息

Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "Giovanni Pascale"-IRCCS-ITALY, Naples, Italy.

Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.

出版信息

Cell Death Dis. 2014 Jul 3;5(7):e1310. doi: 10.1038/cddis.2014.269.

DOI:10.1038/cddis.2014.269

PMID:24991762

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4123065/

Abstract

Treatment of metastatic renal cell carcinoma (mRCC) has improved significantly with the advent of agents targeting the mTOR pathway, such as temsirolimus and everolimus. However, their efficacy is thought to be limited by feedback loops and crosstalk with other pathways leading to the development of drug resistance. As CXCR4-CXCL12-CXCR7 axis has been described to have a crucial role in renal cancer; the crosstalk between the mTOR pathway and the CXCR4-CXCL12-CXCR7 chemokine receptor axis has been investigated in human renal cancer cells. In SN12C and A498, the common CXCR4-CXCR7 ligand, CXCL12, and the exclusive CXCR7 ligand, CXCL11, activated mTOR through P70S6K and 4EBP1 targets. The mTOR activation was specifically inhibited by CXCR4 antagonists (AMD3100, anti-CXCR4-12G5 and Peptide R, a newly developed CXCR4 antagonist) and CXCR7 antagonists (anti-CXCR7-12G8 and CCX771, CXCR7 inhibitor). To investigate the functional role of CXCR4, CXCR7 and mTOR in human renal cancer cells, both migration and wound healing were evaluated. SN12C and A498 cells migrated toward CXCL12 and CXCL11; CXCR4 and CXCR7 inhibitors impaired migration and treatment with mTOR inhibitor, RAD001, further inhibited it. Moreover, CXCL12 and CXCL11 induced wound healing while was impaired by AMD3100, the anti CXCR7 and RAD001. In SN12C and A498 cells, CXCL12 and CXCL11 promoted actin reorganization characterized by thin spikes at the cell periphery, whereas AMD3100 and anti-CXCR7 impaired CXCL12/CXCL11-induced actin polymerization, and RAD001 treatment further reduced it. In addition, when cell growth was evaluated in the presence of CXCL12, CXCL11 and mTOR inhibitors, an additive effect was demonstrated with the CXCR4, CXCR7 antagonists and RAD001. RAD001-resistant SN12C and A498 cells recovered RAD001 sensitivity in the presence of CXCR4 and CXCR7 antagonists. In conclusion, the entire axis CXCR4-CXCL12-CXCR7 regulates mTOR signaling in renal cancer cells offering new therapeutic opportunities and targets to overcome resistance to mTOR inhibitors.

摘要

随着靶向mTOR通路的药物（如替西罗莫司和依维莫司）的出现，转移性肾细胞癌（mRCC）的治疗有了显著改善。然而，它们的疗效被认为受到反馈回路以及与其他导致耐药性产生的通路的串扰的限制。由于CXCR4 - CXCL12 - CXCR7轴已被描述在肾癌中起关键作用；因此在人肾癌细胞中研究了mTOR通路与CXCR4 - CXCL12 - CXCR7趋化因子受体轴之间的串扰。在SN12C和A498细胞中，常见的CXCR4 - CXCR7配体CXCL12以及唯一的CXCR7配体CXCL11通过P70S6K和4EBP1靶点激活mTOR。mTOR的激活被CXCR4拮抗剂（AMD3100、抗CXCR4 - 12G5和肽R，一种新开发的CXCR4拮抗剂）和CXCR7拮抗剂（抗CXCR7 - 12G8和CCX771，CXCR7抑制剂）特异性抑制。为了研究CXCR4、CXCR7和mTOR在人肾癌细胞中的功能作用，评估了迁移和伤口愈合情况。SN12C和A498细胞向CXCL12和CXCL11迁移；CXCR4和CXCR7抑制剂损害迁移，并且用mTOR抑制剂RAD001处理进一步抑制迁移。此外，CXCL12和CXCL11诱导伤口愈合，但被AMD3100、抗CXCR7和RAD001损害。在SN12C和A498细胞中，CXCL12和CXCL11促进肌动蛋白重组，其特征是在细胞周边有细的棘突，而AMD3100和抗CXCR7损害CXCL12/CXCL11诱导的肌动蛋白聚合，并且RAD001处理进一步降低这种聚合。另外，当在CXCL12、CXCL11和mTOR抑制剂存在的情况下评估细胞生长时，CXCR4、CXCR7拮抗剂和RAD001表现出相加效应。RAD001耐药的SN12C和A498细胞在存在CXCR4和CXCR7拮抗剂的情况下恢复了对RAD001的敏感性。总之，整个CXCR4 - CXCL12 - CXCR7轴调节肾癌细胞中的mTOR信号传导，为克服对mTOR抑制剂的耐药性提供了新的治疗机会和靶点。