Disruption of transient receptor potential canonical channel 1 causes incomplete cytokinesis and slows the growth of human malignant gliomas.
Disruption of transient receptor potential canonical channel 1 causes incomplete cytokinesis and slows the growth of human malignant gliomas.
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DOI：
10.1002/glia.20994
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发表时间：
2010-08
期刊：
影响因子：
6.2
通讯作者：
Sontheimer, Harald
中科院分区：
文献类型：
--
作者：
Bomben, Valerie C.;Sontheimer, Harald
尽管经过了几十年的研究，但原发性脑肿瘤、胶质瘤缺乏有效的治疗选择，并提出了巨大的临床挑战。尤其是恶性程度最高的多形性胶质母细胞瘤，广泛增殖，细胞分裂不完全，形成多核细胞。我们现在提出的证据表明，多核胶质瘤细胞是由于瞬时受体电位规范1(TRPC1)通道、参与激动剂诱导的钙内流和细胞内钙库重新加载的质膜蛋白功能丧失所致。药物抑制或shRNA介导的TRPC1抑制导致D54 MG胶质瘤细胞功能通道的丧失和钙离子内流。这与细胞增殖减少有关，而且常常与细胞分裂不完全有关。由此产生的多核细胞与患者活检中发现的细胞相似。在侧翼肿瘤模型中，当使用多西环素诱导的shRNA敲除方法破坏TRPC1的表达时，肿瘤大小显著减小。这些结果表明，TRPC1通道在胶质瘤细胞分裂中发挥重要作用，很可能是通过调节胞质分裂过程中的钙信号。
Despite decades of research, primary brain tumors, gliomas, lack effective treatment options and present a huge clinical challenge. Particularly, the most malignant subtype, Glioblastoma multiforme, proliferates extensively and cells often undergo incomplete cell divisions, resulting in multinucleated cells. We now present evidence that multinucleated glioma cells result from the functional loss of transient receptor potential canonical 1 (TRPC1) channels, plasma membrane proteins involved in agonist-induced calcium entry and reloading of intracellular Ca2+ stores. Pharmacological inhibition or shRNA mediated suppression of TRPC1 causes loss of functional channels and store-operated calcium entry in D54MG glioma cells. This is associated with reduced cell proliferation and, frequently, with incomplete cell division. The resulting multinucleated cells are reminiscent of those found in patient biopsies. In a flank tumor model, tumor size was significantly decreased when TRPC1 expression was disrupted using a doxycycline inducible shRNA knockdown approach. These results suggest that TRPC1 channels play an important role in glioma cell division most likely by regulating calcium signaling during cytokinesis.
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