由英國(guó)萊斯特大學(xué)領(lǐng)導(dǎo)的一個(gè)研究小組已證明某些腫瘤細(xì)胞對(duì)蛋白質(zhì)P21特別敏感,。這種蛋白質(zhì)通常會(huì)迫使正常細(xì)胞與癌細(xì)胞停止分裂,，但最近研究表明在某些情況下,，P21也可以殺死癌細(xì)胞。
然而,，科學(xué)家們一直不清楚這是如何發(fā)生的,。
萊斯特大學(xué)生物化學(xué)系Salvador Macip研究員說(shuō)：“如果我們可以利用P21的這種“殺傷力”，那么我們可以開發(fā)出旨在提高P21水平的癌癥新療法,。
現(xiàn)在,，英國(guó)萊斯特和加的夫大學(xué)、美國(guó)南卡羅來(lái)納大學(xué)和瑞典卡羅林斯卡醫(yī)學(xué)院的研究團(tuán)隊(duì)發(fā)現(xiàn)肉瘤細(xì)胞往往死在P21,，這是由其線粒體對(duì)氧化劑的敏感性決定的,。
他們的研究結(jié)果發(fā)表在Journal of Biological Chemistry雜志上。這項(xiàng)研究是由湄公河委員會(huì),、美國(guó)國(guó)立衛(wèi)生研究院,、國(guó)家科學(xué)技術(shù)委員會(huì)和瑞典癌癥協(xié)會(huì)資助。
Macip博士補(bǔ)充說(shuō)：“我們的研究還表明P21能殺死細(xì)胞,，即使在缺乏p53的情況下,，p53調(diào)控細(xì)胞死亡的一種蛋白質(zhì)，其在大多數(shù)癌癥處于失活狀態(tài)”,。
這表明某些類型的癌癥比如肉瘤對(duì)能增加p21水平的藥物會(huì)有反應(yīng),，即使這些癌癥類型換患者體內(nèi)P53是失活的。這些P21的療法副作用應(yīng)該很小,，因?yàn)槲覀兊膶?shí)驗(yàn)結(jié)果表明,，P21并不導(dǎo)致正常細(xì)胞死亡。
現(xiàn)在已經(jīng)有藥物可有選擇性地增加p21的水平,。我們的研究結(jié)果測(cè)試這些藥物對(duì)某些類型癌癥的治療效果,。（生物谷：Bioon）
doi:10.1074/jbc.M111.250357
PMC:
PMID:
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.
p21Waf1/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.
