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【Nature】科学家发现癌症肿瘤抗药机理

现在治疗癌症的主要方法之一是化学疗法，但相关药物对不同的癌症患者效果差异也很大。对此，美国两个研究小组最新发布的研究成果均指出，一种名为FBW7的基因发生变异可能是癌症肿瘤具有抗药性的原因，这一发现将有助医生对不同类型的癌症患者对症下药。 这两个研究小组的报告发表在最新一期英国《自然》杂志上，其中一个小组从研究紫杉醇等抗癌药物的效果入手，紫杉醇会使肿瘤细胞无法分裂并最终死亡，这种药物通过降低一种名为MCL1的蛋白质含量而起作用，但如果FBW7基因发生变异或者缺失，这种蛋白质的含量就会居高不下，紫杉醇也就无法起到应有的抗癌作用。 另一个研究小组则从研究俗称“血癌”的白血病入手，结果得出同样的结论，携带有已变异的FBW7基因的患者体内癌细胞往往更难被消除。 研究人员说，由这个基因的变异所导致的抗药性可能出现在多种癌症中，如乳腺癌和肠癌等，但仍然可以通过其他一些方法来应对这种抗药性。因此，在癌症治疗中可能需要先进行基因检测，根据患者携带基因的不同，来确定使用哪些药物才会起到更好的治疗效果。（来源：新华网 黄堃）
Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics1. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas1. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms2. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear2. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lackedFBW7[/i] or had loss-of-function mutations in FBW7[/i], conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7[/i]inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.

SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destructionThe effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7[/i], which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer1 and T-cell acute lymphoblastic leukaemia (T-ALL)2. In line with these genomic data, engineered deletion ofFbw7[/i] in mouse T cells results in T-ALL3, 4, 5, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun

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作者:admin@医学,生命科学    2011-03-06 11:04
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