Division of Cell and Developmental Biology, University of Dundee, Dow Street, Dundee, DD1 5EH, UK.
J Cell Sci. 2012 Feb 15;125(Pt 4):887-95. doi: 10.1242/jcs.091843. Epub 2012 Mar 7.
Colorectal cancers commonly carry truncation mutations in the adenomatous polyposis coli (APC) gene. The APC protein contributes to the stabilization of microtubules. Consistently, microtubules in cells lacking APC depolymerize more readily in response to microtubule-destabilizing drugs. This raises the possibility that such agents are suitable for treatment of APC-deficient cancers. However, APC-deficient cells have a compromised spindle assembly checkpoint, which renders them less sensitive to killing by microtubule poisons whose toxicity relies on the induction of prolonged mitotic arrest. Here, we describe the novel discovery that the clinically used microtubule-depolymerizing drug vinorelbine (Navelbine) kills APC-deficient cells in culture and in intestinal tissue more effectively than it kills wild-type cells. This is due to the ability of vinorelbine to kill cells in interphase independently of mitotic arrest. Consistent with a role for p53 in cell death in interphase, depletion of p53 renders cells less sensitive to vinorelbine, but only in the presence of wild-type APC. The pro-apoptotic protein BIM (also known as BCL2L11) is recruited to mitochondria in response to vinorelbine, where it can inhibit the anti-apoptotic protein BCL2, suggesting that BIM mediates vinorelbine-induced cell death. This recruitment of BIM is enhanced in cells lacking APC. Consistently, BIM depletion dampens the selective effect of vinorelbine on these cells. Our findings reveal that vinorelbine is a potential therapeutic agent for colorectal cancer, but they also illustrate the importance of the APC tumour suppressor status when predicting therapeutic efficacy.
结直肠癌通常携带腺瘤性结肠息肉病（APC）基因的截断突变。APC 蛋白有助于微管的稳定。一致地，缺乏 APC 的细胞中的微管在响应微管不稳定药物时更容易解聚。这就提出了这样一种可能性，即这些药物可能适合治疗 APC 缺失型癌症。然而，APC 缺失的细胞有一个受损的纺锤体组装检查点，这使得它们对微管毒物的杀伤作用不太敏感，而这些毒物的毒性依赖于诱导长时间的有丝分裂阻滞。在这里，我们描述了一个新的发现，即临床上使用的微管解聚药物长春瑞滨（Navelbine）在培养中和肠组织中杀死 APC 缺失型细胞比杀死野生型细胞更有效。这是由于长春瑞滨能够在有丝分裂阻滞之外独立地杀死细胞。与 p53 在有丝分裂间期细胞死亡中的作用一致，p53 的耗竭使细胞对长春瑞滨的敏感性降低，但只有在存在野生型 APC 的情况下。促凋亡蛋白 BIM（也称为 BCL2L11）被募集到线粒体以响应长春瑞滨，在那里它可以抑制抗凋亡蛋白 BCL2，这表明 BIM 介导了长春瑞滨诱导的细胞死亡。这种 BIM 的募集在缺乏 APC 的细胞中增强。一致地，BIM 的耗竭减弱了长春瑞滨对这些细胞的选择性影响。我们的发现揭示了长春瑞滨是结直肠癌的一种潜在治疗药物，但它们也说明了 APC 肿瘤抑制状态在预测治疗效果时的重要性。
