Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells
Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells
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DOI：
10.1016/j.ejca.2008.02.043
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发表时间：
2008-05-01
影响因子：
8.4
通讯作者：
Saiki, Izuo
中科院分区：
文献类型：
--
作者：
Hashimoto, Isaya;Koizumi, Keiichi;Saiki, Izuo
进展期胃癌，尤其是腹膜播散患者，即使经过任何治疗，预后也很差。现在已知趋化因子在癌症生长和转移中发挥重要作用。我们最近报道趋化因子CXCL12在胃癌腹膜癌发展中发挥重要作用。在本研究中，我们研究了趋化因子CXCL12诱导的腹膜癌病中涉及的信号通路。Akt被趋化因子CXCL12快速而强烈地磷酸化。 CXCL12 还诱导位于 Akt 下游的哺乳动物雷帕霉素靶点 (mTOR) 通路中的 p70S6K (S6K) 和真核起始因子 4E 结合蛋白 1 (4E-BP1) 的激活，从而增强腹膜播散性胃癌 NUGC4 中 MMP 产生、细胞迁移和细胞生长等转移特性。 细胞。此外，mTOR抑制剂雷帕霉素不仅能显着抑制迁移和MMP产生，还能诱导11型程序性细胞死亡，即自噬性细胞死亡。在本研究中，我们首次证明mTOR通路在腹膜癌病的发生发展中发挥着核心作用，阻断该通路可诱导播散性胃癌中的自噬性细胞死亡。因此，阻断CXCR4/mTOR信号通路可能有助于未来开发更有效的治疗腹膜播散性胃癌的策略。 (c) 2008 Elsevier Ltd. 保留所有权利。
Patients with advanced gastric carcinoma, especially peritoneal dissemination, have a poor prognosis even after any treatment. Chemokines are now known to play an important role in cancer growth and metastasis. We recently reported that the chemokine CXCL12 plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. In this study, we investigated signalling pathway involved in the peritoneal carcinomatosis induced by chemokine CXCL12.Akt was rapidly and strongly phosphorylated by chemokine CXCL12. CXCL12 also induced the activation of p70S6K (S6K) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1) included in mammalian target of rapamycin (mTOR) pathways which are located downstream of Akt, resulting in enhancements of metastatic properties such as MMP production, cell migration and cell growth in peritoneal disseminated gastric cancer, NUGC4 cells. Furthermore, mTOR inhibitor rapamycin not only drastically inhibited migration and MMP production, but also induced type 11 programmed cell death, autophagic cell death.In the present study, we have shown for the first time that the mTOR pathway plays a central role in the development of peritoneal carcinomatosis, and blocking this pathway induces autophagic cell death in disseminated gastric cancer. Therefore, blocking on the CXCR4/mTOR signalling pathway may be useful for the future development of a more effective therapeutic strategy for gastric cancer involved in peritoneal dissemination. (c) 2008 Elsevier Ltd. All rights reserved.