Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo, Japan.
Oncogene. 2012 Jan 12;31(2):135-48. doi: 10.1038/onc.2011.235. Epub 2011 Jun 20.
The formation of the bipolar spindle is responsible for accurate chromosomal segregation during mitosis. The dynamic instability of microtubules has an important role in this process, and has been shown to be an effective target for cancer chemotherapy. Several agents that target non-microtubule mitotic proteins, including the motor protein Eg5, Aurora kinases and Polo-like kinases, are currently being developed as chemotherapeutic drugs. However, because the efficacies of these drugs remain elusive, new molecular targets that have essential roles in tumor cells are desired. Here, we provide in vivo evidence that transforming acidic coiled-coil-3 (Tacc3) is a potential target for cancer chemotherapy. Using MRI, we showed that Tacc3 loss led to the regression of mouse thymic lymphoma in vivo, which was accompanied by massive apoptosis. By contrast, normal tissues, including the thymus, showed no overt abnormalities, despite high Tacc3 expression. in vitro analysis indicated that Tacc3 depletion induced multi-polar spindle formation, which led to mitotic arrest, followed by apoptosis. Similar responses have been observed in Burkitt's lymphoma and T-ALL. These results show that Tacc3 is a vulnerable component of the spindle assembly in lymphoma cells and is a promising cancer chemotherapy target.
双极纺锤体的形成负责有丝分裂过程中染色体的准确分离。微管的动态不稳定性在这个过程中起着重要作用，并且已被证明是癌症化疗的有效靶点。目前正在开发几种针对非微管有丝分裂蛋白的药物，包括马达蛋白 Eg5、Aurora 激酶和 Polo 样激酶，这些药物被开发为化疗药物。然而，由于这些药物的疗效仍然难以捉摸，因此需要寻找在肿瘤细胞中具有重要作用的新的分子靶点。在这里，我们提供了体内证据，证明转化酸性卷曲螺旋-3（Tacc3）是癌症化疗的潜在靶点。我们通过 MRI 显示，Tacc3 缺失导致体内小鼠胸腺淋巴瘤的消退，同时伴随着大量细胞凋亡。相比之下，尽管 Tacc3 表达水平较高，但正常组织（包括胸腺）没有明显异常。体外分析表明，Tacc3 耗竭诱导多极纺锤体形成，导致有丝分裂停滞，随后发生细胞凋亡。在伯基特淋巴瘤和 T-ALL 中也观察到了类似的反应。这些结果表明，Tacc3 是淋巴瘤细胞中纺锤体组装的脆弱组成部分，是一种很有前途的癌症化疗靶点。
