CR-UK Beatson Institute of Cancer Research, Glasgow, UK.
Oncogene. 2010 Dec 9;29(49):6418-27. doi: 10.1038/onc.2010.373. Epub 2010 Aug 23.
Mutations in the adenomatous polyposis coli (APC) tumour suppressor are the key initiating event of colorectal cancer. Although the control of WNT signalling is well established as a central tumour-suppressive function, the significance of APC in regulating chromosome instability is less well established. In this study, we test whether APC-deficient cells have a functional spindle assembly checkpoint (SAC) in vivo by examining the response of these cells to Taxol and Vinorelbine. We also show for the first time that APC deficiency compromises the arrest response to Taxol in vivo. This effect is independent of the role that APC has in WNT signalling. At higher levels of Taxol, APC-deficient cells arrest as efficiently as wild-type cells. Importantly, this dose of Taxol strongly suppresses intestinal tumourigenesis in models of benign (APC(Min/+) mouse) and invasive (AhCreER(+)APC(fl/+)PTEN(fl/fl)) cancer. In contrast to intestinal enterocytes with a general SAC defect because of Bub1 (budding uninhibited by benzimidazole 1) deletion, APC-deficient enterocytes arrest equivalently to wild type when treated with Vinorelbine. This suggests that the failed arrest in response to Taxol is because of a specific defect in microtubule stabilization following Taxol treatment rather than a general role of the APC protein in the mitotic spindle checkpoint. In summary, this study clarifies the role of APC as a mitotic spindle checkpoint protein in vivo and shows that APC-deficient cells have a compromised response to Taxol.
腺瘤性结肠息肉病（APC）肿瘤抑制因子的突变是结直肠癌的关键起始事件。虽然 WNT 信号的控制已被明确为一种中央肿瘤抑制功能，但 APC 调节染色体不稳定性的意义尚未得到很好的确定。在这项研究中，我们通过检查这些细胞对紫杉醇和长春瑞滨的反应来测试 APC 缺陷细胞是否在体内具有功能性纺锤体组装检查点（SAC）。我们还首次表明，APC 缺陷会损害体内紫杉醇的阻滞反应。这种效应独立于 APC 在 WNT 信号中的作用。在较高水平的紫杉醇下，APC 缺陷细胞的阻滞效率与野生型细胞相当。重要的是，这种剂量的紫杉醇强烈抑制良性（APC(Min/+)小鼠）和侵袭性（AhCreER(+)APC(fl/+)PTEN(fl/fl)）癌症模型中的肠道肿瘤发生。与由于 Bub1（苯并咪唑 1 抑制不受抑制）缺失而具有普遍 SAC 缺陷的肠细胞不同，用长春瑞滨处理时，APC 缺陷的肠细胞与野生型细胞同等地阻滞。这表明，紫杉醇处理后微管稳定性的特定缺陷导致紫杉醇应答中的阻滞失败，而不是 APC 蛋白在有丝分裂纺锤体检查点中的一般作用。总之，这项研究阐明了 APC 在体内作为有丝分裂纺锤体检查点蛋白的作用，并表明 APC 缺陷细胞对紫杉醇的反应受损。
