Yao R, Kondoh Y, Natsume Y, Yamanaka H, Inoue M, Toki H, Takagi R, Shimizu T, Yamori T, Osada H, Noda T
Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo, Japan.
Chemical Biology Core Facility, RIKEN Advanced Science Institute, Saitama, Japan.
Oncogene. 2014 Aug 14;33(33):4242-52. doi: 10.1038/onc.2013.382. Epub 2013 Sep 30.
The mitotic spindle is assembled by the coordinated action of centrosomes and kinetochore microtubules. An evolutionally conserved protein family, transforming acidic coiled-coil (TACC), has been shown to be involved in this process. In humans, TACC3 is aberrantly expressed in a variety of human cancers, but its biological significance remains to be elucidated. Here, using a novel compound targeting TACC3, spindlactone (SPL), we show that the perturbation of TACC3 selectively inhibited the nucleation of centrosome microtubules in ovarian cancer cells. In contrast to centrosome microtubules, the kinetochore microtubules were robustly assembled, forming ectopic spindle poles that resulted in multipolar spindles. Interestingly, the extensive inhibition of TACC3 partially suppressed the nucleation of kinetochore microtubules. These dose-dependent effects of SPL were consistent with the results observed by the depletion of TACC3 and its binding partner, colonic and hepatic tumor overexpressed gene protein (TOGp). Although these proteins both have roles in the assembly of centrosome and kinetochore microtubules, their contributions were spatiotemporally different. Notably, SPL did not affect spindle assembly in normal cells. Furthermore, the oral administration of SPL significantly suppressed tumor growth in vivo. The unique mechanism of action of SPL not only enables it to be used as a tool to dissect the molecular basis of spindle assembly but also to provide a rationale for the use of TACC3 as a molecular target for cancer treatment. This rationale offers an opportunity to develop new strategies for cancer chemotherapy that overcome the limitations of microtubule toxins and expand their scope and clinical efficacy.
有丝分裂纺锤体由中心体和动粒微管的协同作用组装而成。一个进化上保守的蛋白质家族——转化酸性卷曲螺旋（TACC），已被证明参与了这一过程。在人类中，TACC3在多种人类癌症中异常表达，但其生物学意义仍有待阐明。在此，我们使用一种靶向TACC3的新型化合物——纺锤内酯（SPL），发现TACC3的扰动选择性地抑制了卵巢癌细胞中中心体微管的成核。与中心体微管不同，动粒微管大量组装，形成异位纺锤极，导致多极纺锤体。有趣的是，对TACC3的广泛抑制部分抑制了动粒微管的成核。SPL的这些剂量依赖性效应与通过敲低TACC3及其结合伙伴结肠和肝脏肿瘤过表达基因蛋白（TOGp）所观察到的结果一致。尽管这些蛋白质在中心体和动粒微管的组装中都起作用，但它们的贡献在时空上有所不同。值得注意的是，SPL不影响正常细胞中的纺锤体组装。此外，口服SPL可显著抑制体内肿瘤生长。SPL独特的作用机制不仅使其能够用作剖析纺锤体组装分子基础的工具，还为将TACC3用作癌症治疗的分子靶点提供了理论依据。这一理论依据为开发新的癌症化疗策略提供了机会，可克服微管毒素的局限性并扩大其范围和临床疗效。
