自英國(guó)Beatson癌癥研究所的研究人員在一項(xiàng)新研究中證實(shí),，奪去癌細(xì)胞的一種關(guān)鍵氨基酸可顯著削弱它們的生長(zhǎng)和增殖能力。這一研究發(fā)現(xiàn)在線發(fā)表在12月16日的《自然》（Nature）雜志上,。
Beatson癌癥研究所的科學(xué)家們研究了當(dāng)缺乏絲氨酸時(shí)癌細(xì)胞能夠生存并繼續(xù)生長(zhǎng)的機(jī)制。細(xì)胞通常能夠自己生成絲氨酸,，然而研究小組發(fā)現(xiàn)缺乏p53蛋白的細(xì)胞（至少一半的癌癥存在這種缺陷）則無(wú)法適應(yīng)這一轉(zhuǎn)變,，因此其生長(zhǎng)速度大為放緩。
p53蛋白最早是被英國(guó)癌癥研究院的科學(xué)家們所發(fā)現(xiàn),，由于它能夠停止受損細(xì)胞生長(zhǎng),，激活DNA修復(fù)或啟動(dòng)細(xì)胞死亡，通常被稱(chēng)為是“基因組的衛(wèi)士”,。
研究結(jié)果表明,，通過(guò)靶向癌細(xì)胞生成生長(zhǎng)所需能量及構(gòu)件的途徑，可以開(kāi)發(fā)出治療癌癥的新方法,。
英國(guó)Beatson癌癥研究所首席研究員Oliver Maddocks博士說(shuō)：“我們知道p53蛋白可以阻止癌細(xì)胞生長(zhǎng),，但我們也越來(lái)越認(rèn)識(shí)到p53是一種具有‘分裂人格’的基因,。當(dāng)細(xì)胞缺乏關(guān)鍵營(yíng)養(yǎng)時(shí)，p53會(huì)幫助它們適應(yīng),，并有可能幫助癌細(xì)胞生存,。“
“了解細(xì)胞代謝與p53之間的相互作用，或許有助于我們確定治療癌癥的新途徑,。減少癌細(xì)胞的絲氨酸利用率,，尤其是缺失p53的癌細(xì)胞，是一種有前景的新概念,，然而確定這是否能對(duì)患者起作用還有一個(gè)漫長(zhǎng)的過(guò)程,。”
癌細(xì)胞攝取大量的絲氨酸，以它作為基本構(gòu)件快速生長(zhǎng)并生成新細(xì)胞,。本研究是建立在Beatson研究所過(guò)往的研究工作基礎(chǔ)上：癌細(xì)胞中絲氨酸的水平控制了能量生成的一個(gè)關(guān)鍵步驟,。
英國(guó)癌癥研究院的首席科學(xué)家Nic Jones教授說(shuō)：“這項(xiàng)工作表明，在英國(guó)癌癥研究中心的科學(xué)家們發(fā)現(xiàn)p53的30年之后,，我們?nèi)匀豢梢粤私獾礁鄍53在癌癥中發(fā)揮作用的信息,。”
“了解癌細(xì)胞能夠生成額外能量和分子構(gòu)件快速生長(zhǎng)的機(jī)制，正變成一個(gè)重要的研究領(lǐng)域,。擾亂細(xì)胞代謝有可能導(dǎo)致全新的治療癌癥的藥物庫(kù),，英國(guó)癌癥研究院處于本研究的前沿。”(生物谷Bioon.com)
doi:10.1038/nature11743
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PMID:
Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells
Oliver D. K. Maddocks, Celia R. Berkers, Susan M. Mason, Liang Zheng, Karen Blyth, Eyal Gottlieb & Karen H. Vousden
Cancer cells acquire distinct metabolic adaptations to survive stress associated with tumour growth and to satisfy the anabolic demands of proliferation. The tumour suppressor protein p53 (also known as TP53) influences a range of cellular metabolic processes, including glycolysis1, 2, oxidative phosphorylation3, glutaminolysis4, 5 and anti-oxidant response6. In contrast to its role in promoting apoptosis during DNA-damaging stress, p53 can promote cell survival during metabolic stress7, a function that may contribute not only to tumour suppression but also to non-cancer-associated functions of p538. Here we show that human cancer cells rapidly use exogenous serine and that serine deprivation triggered activation of the serine synthesis pathway and rapidly suppressed aerobic glycolysis, resulting in an increased flux to the tricarboxylic acid cycle. Transient p53-p21 (also known as CDKN1A) activation and cell-cycle arrest promoted cell survival by efficiently channelling depleted serine stores to glutathione synthesis, thus preserving cellular anti-oxidant capacity. Cells lacking p53 failed to complete the response to serine depletion, resulting in oxidative stress, reduced viability and severely impaired proliferation. The role of p53 in supporting cancer cell proliferation under serine starvation was translated to an in vivo model, indicating that serine depletion has a potential role in the treatment of p53-deficient tumours.
