JBC：科学家解开癌细胞死亡之谜的关键

由英国莱斯特大学领导的一个研究小组已证明某些肿瘤细胞对蛋白质P21特别敏感。这种蛋白质通常会迫使正常细胞与癌细胞停止分裂，但最近研究表明在某些情况下，P21也可以杀死癌细胞。

然而，科学家们一直不清楚这是如何发生的。

莱斯特大学生物化学系Salvador Macip研究员说：“如果我们可以利用P21的这种“杀伤力”，那么我们可以开发出旨在提高P21水平的癌症新疗法。

现在，英国莱斯特和加的夫大学、美国南卡罗来纳大学和瑞典卡罗林斯卡医学院的研究团队发现肉瘤细胞往往死在P21，这是由其线粒体对氧化剂的敏感性决定的。

他们的研究结果发表在Journal of Biological Chemistry杂志上。这项研究是由湄公河委员会、美国国立卫生研究院、国家科学技术委员会和瑞典癌症协会资助。

Macip博士补充说：“我们的研究还表明P21能杀死细胞，即使在缺乏p53的情况下，p53调控细胞死亡的一种蛋白质，其在大多数癌症处于失活状态”。

这表明某些类型的癌症比如肉瘤对能增加p21水平的药物会有反应，即使这些癌症类型换患者体内P53是失活的。这些P21的疗法副作用应该很小，因为我们的实验结果表明，P21并不导致正常细胞死亡。

现在已经有药物可有选择性地增加p21的水平。我们的研究结果测试这些药物对某些类型癌症的治疗效果。（生物谷：Bioon）

doi:10.1074/jbc.M111.250357
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Reactive oxygen species and mitochondrial sensitivity to oxidative stress determine induction of cancer cell death by p21

Masgras I, Carrera S, de Verdier PJ, Brennan P, Majid A, Makhtar W, Tulchinksy E, Jones GD, Roninson IB, Macip S.

p21^{Waf1/Cip1/Sdi1} is a cyclin-dependent kinase inhibitor that mediates cell cycle arrest. Prolonged p21 up-regulation induces a senescent phenotype in normal and cancer cells, accompanied by an increase in intracellular reactive oxygen species (ROS). However, it has been shown recently that p21 expression can also lead to cell death in certain models. The mechanisms involved in this process are not fully understood. Here, we describe an induction of apoptosis by p21 in sarcoma cell lines that is p53-independent and can be ameliorated with antioxidants. Similar levels of p21 and ROS caused senescence in the absence of significant death in other cancer cell lines, suggesting a cell-specific response. We also found that cells undergoing p21-dependent cell death had higher sensitivity to oxidants and a specific pattern of mitochondrial polarization changes. Consistent with this, apoptosis could be blocked with targeted expression of catalase in the mitochondria of these cells. We propose that the balance between cancer cell death and arrest after p21 up-regulation depends on the specific effects of p21-induced ROS on the mitochondria. This suggests that selective up-regulation of p21 in cancer cells could be a successful therapeutic intervention for sarcomas and tumors with lower resistance to mitochondrial oxidative damage, regardless of p53 status.