Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival.
Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival.
复制标题
DOI：
10.1158/0008-5472.can-09-2886
复制
发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Lee CJ
中科院分区：
文献类型：
--
作者：
Kang SS;Han KS;Ku BM;Lee YK;Hong J;Shin HY;Almonte AG;Woo DH;Brat DJ;Hwang EM;Yoo SH;Chung CK;Park SH;Paek SH;Roh EJ;Lee SJ;Park JY;Traynelis SF;Lee CJ
钙信号在许多细胞过程中是一个重要的决定因素，特别是在癌细胞的增殖、运动和侵袭过程中。胶质母细胞瘤是最致命的脑癌，其平均生存期不到一年，最突出的细胞特征是这些细胞迁移到并侵袭邻近组织的能力。我们假设，干扰钙信号通路会降低这些细胞的迁移倾向。因此，我们研究了胶质母细胞瘤细胞对不同受体酪氨酸激酶(RTK)和G蛋白偶联受体(GPCR)激动剂反应的详细的钙信号通路。在此，我们报道了已知的兰尼定受体(RyRs)激活剂咖啡因，通过选择性靶向IP3R亚型3(IP3R3)，矛盾地抑制了三磷酸肌醇受体(IP3R)介导的钙升高，而IP3R3的mRNA表达在胶质母细胞瘤细胞中显著增加。因此，通过抑制IP3R3介导的钙释放，咖啡因被发现在刮除运动、Matrigel侵袭、软琼脂和脑片植入试验中抑制各种胶质母细胞瘤细胞系的侵袭和迁移。在小鼠胶质母细胞瘤的异种移植模型中，通过饮用水摄入咖啡因大大延长了受试者动物的平均存活时间。这些发现表明IP3R3是治疗胶质母细胞瘤的新靶点，咖啡因可能是一种有用的辅助疗法，通过选择性靶向IP3R3来减缓胶质母细胞瘤的侵袭和迁移。
Ca2+ signaling is an important determining factor in many cellular processes, especially in cancer cell proliferation, motility and invasion. Glioblastoma is the deadliest brain cancer with its average survival time of less than a year, with the most prominent cellular feature being the ability of these cells to migrate to and invade the neighboring tissue. We hypothesized that disturbing the Ca2+ signaling pathway would decrease the propensity for these cells to migrate. Thus, we investigated the detailed Ca2+ signaling pathway of the glioblastoma cells in response to various receptor tyrosine kinases (RTK) and G-protein coupled receptor (GPCR) agonists. Here we report that caffeine, which is a well-known activator of ryanodine receptors (RyRs), paradoxically inhibits inositol-1, 4, 5-triphospate receptor(IP3R)-mediated Ca2+ increase by selectively targeting IP3R subtype 3(IP3R3), whose mRNA expression is significantly increased in glioblastoma cells. Consequently, by inhibiting IP3R3-mediated Ca2+ release, caffeine was found to inhibit the invasion and migration of various glioblastoma cell lines in scrape motility, Matrigel invasion, soft agar, and brain slice implantation assays. In a mouse xenograft model of glioblastoma, caffeine intake via drinking water greatly increased mean survival duration of subject animals. These findings propose IP3R3 as a novel target for glioblastoma treatment and that caffeine may be a useful adjunct therapy that slows glioblastoma invasion and migration by selectively targeting IP3R3.