化療和輻射引起癌細(xì)胞氧化應(yīng)激,，進(jìn)而殺死腫瘤細(xì)胞,。南加州大學(xué)的一項(xiàng)新的研究表明,，保護(hù)癌癥和其他細(xì)胞免受應(yīng)激壓力的一種蛋白質(zhì)有一天能夠幫助醫(yī)生打破癌細(xì)胞的防御能力,，使得癌細(xì)胞對(duì)相應(yīng)治療更敏感,。
南加州大學(xué)教授Kelvin J. A. Davies率領(lǐng)的研究團(tuán)隊(duì)完成的最新研究證實(shí)蛋白質(zhì)Nrf2能增強(qiáng)細(xì)胞應(yīng)對(duì)氧化應(yīng)激的能力,。相關(guān)研究論文發(fā)表在3月23日的《生物化學(xué)雜志》上,。
氧化應(yīng)激是指體內(nèi)氧化與抗氧化作用失衡，傾向于氧化,，導(dǎo)致中性粒細(xì)胞炎性浸潤(rùn),，蛋白酶分泌增加，產(chǎn)生大量氧化中間產(chǎn)物,。氧化應(yīng)激是由自由基在體內(nèi)產(chǎn)生的一種負(fù)面作用,，并被認(rèn)為是導(dǎo)致衰老和疾病的一個(gè)重要因素。
Davies說(shuō)：“在癌細(xì)胞中,，如果有一天能有選擇性地關(guān)閉Nrf2蛋白,，化療和放射治療可能會(huì)變得更有效”。
Nrf2是一種轉(zhuǎn)錄因子蛋白質(zhì),，Davies實(shí)驗(yàn)室的研究工作表明在氧化應(yīng)激過(guò)程中,，蛋白酶和蛋白酶體調(diào)節(jié)因子（PA28）的生成是由Nrf2控制的。反過(guò)來(lái),，蛋白酶是一個(gè)大的蛋白質(zhì)酶,，能分解氧化的蛋白，氧化的蛋白積累的話(huà)會(huì)導(dǎo)致細(xì)胞死亡,。
當(dāng)腫瘤細(xì)胞氧化應(yīng)激反應(yīng)增加（實(shí)驗(yàn)室中用過(guò)氧化氫刺激腫瘤細(xì)胞,，過(guò)氧化氫放療和化療過(guò)程中主要產(chǎn)物）時(shí)，Davies和他的團(tuán)隊(duì)發(fā)現(xiàn)細(xì)胞Nrf2會(huì)加速蛋白酶的產(chǎn)生,。
然后研究人員通過(guò)各種化學(xué)和遺傳抑制劑阻斷Nrf2來(lái)測(cè)試他們的研究結(jié)果,，結(jié)果發(fā)現(xiàn)Nrf2被抑制后，細(xì)胞生成蛋白酶以及處理雙氧水的能力減弱,。
在正常細(xì)胞中,，Nrf2允許蛋白酶連續(xù)生成以應(yīng)對(duì)不斷變化的氧化環(huán)境。但這種能力隨著衰老可能會(huì)下降,，使年長(zhǎng)者應(yīng)對(duì)應(yīng)激的能力下降,。
Davies說(shuō)：我們希望能夠在正常細(xì)胞中扭轉(zhuǎn)這種下降趨勢(shì)，降低癌細(xì)胞中Nrf2的表達(dá),，使癌細(xì)胞的抗應(yīng)激能力下降,，更容易死于放療和化療。（生物谷：Bioon）
doi:10.1074/jbc.M111.277145
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Nrf2-dependent Induction of Proteasome and Pa28αβ Regulator Are Required for Adaptation to Oxidative Stress
Andrew M. Pickering§, Robert A. Linder§, Hongqiao Zhang, Henry J. Forman and Kelvin J. A. Davies§,1
The ability to adapt to acute oxidative stress (e.g. H2O2, peroxynitrite, menadione, and paraquat) through transient alterations in gene expression is an important component of cellular defense mechanisms. We show that such adaptation includes Nrf2-dependent increases in cellular capacity to degrade oxidized proteins that are attributable to increased expression of the 20 S proteasome and the Pa28αβ (11 S) proteasome regulator. Increased cellular levels of Nrf2, translocation of Nrf2 from the cytoplasm to the nucleus, and increased binding of Nrf2 to antioxidant response elements (AREs) or electrophile response elements (EpREs) in the 5′-untranslated region of the proteasome β5 subunit gene (demonstrated by chromatin immunoprecipitation (or ChIP) assay) are shown to be necessary requirements for increased proteasome/Pa28αβ levels, and for maximal increases in proteolytic capacity and stress resistance; Nrf2 siRNA and the Nrf2 inhibitor retinoic acid both block these adaptive changes and the Nrf2 inducers dl-sulforaphane, lipoic acid, and curcumin all replicate them without oxidant exposure. The immunoproteasome is also induced during oxidative stress adaptation, contributing to overall capacity to degrade oxidized proteins and stress resistance. Two of the three immunoproteasome subunit genes, however, contain no ARE/EpRE elements, and Nrf2 inducers, inhibitors, and siRNA all have minimal effects on immunoproteasome expression during adaptation to oxidative stress. Thus, immunoproteasome appears to be (at most) minimally regulated by the Nrf2 signal transduction pathway.
