來自北京協(xié)和醫(yī)學院／中國醫(yī)學科學院基礎醫(yī)學研究所，廈門大學生科院，哈佛醫(yī)學院等處的研究人員發(fā)現(xiàn)能導致腫瘤細胞發(fā)生有氧糖酵解的蛋白,，幫助解開了腫瘤異常生長代謝之謎，也為治療腫瘤提供了一種新策略,。這一研究成果公布在《美國國家科學院院刊》（PNAS ）雜志上,。
文章的通訊作者是中國醫(yī)學科學院基礎醫(yī)學研究所博士生導師張宏冰教授，以及廈門大學尤涵教授,。張宏冰教授現(xiàn)任中國協(xié)和醫(yī)科大學特聘教授, 博士生導師, 中國醫(yī)學科學院組織工程研究中心客座教授,，主要研究方向是腫瘤信號途徑，抑癌基因等方面的研究,。
腫瘤病人多伴隨有能量消耗高,、體重減輕等代謝紊亂現(xiàn)象。上世紀20年代,，德國諾貝爾獎得主奧托·瓦伯格發(fā)現(xiàn)腫瘤組織的代謝明顯增強,，腫瘤細胞主要依賴糖酵解進行代謝，其耗糖速度遠大于正常細胞,。這一代謝特征究竟是癌癥產(chǎn)生的原因還是癌細胞代謝改變的結果,，則是長期困擾醫(yī)學界的難題。
近年來,，腫瘤代謝異?，F(xiàn)象再次引起人們的重視，這種“瓦伯格效應”又開始成為腫瘤研究的焦點,。哈佛大學科學家發(fā)現(xiàn)主要存在于腫瘤細胞的M2型丙酮酸激酶可促進腫瘤細胞“瓦伯格效應”的發(fā)生,，并對腫瘤的形成和生長起著至關重要的作用，但是腫瘤細胞產(chǎn)生M2型丙酮酸激酶的誘因不甚清楚,。
在這篇文章中,，研究人員發(fā)現(xiàn)異常激活的雷帕霉素靶蛋白（mTOR）通過誘導產(chǎn)生M2型丙酮酸激酶，從而導致腫瘤細胞發(fā)生有氧糖酵解,。這一發(fā)現(xiàn)為治療腫瘤提供了一種新策略,。
張宏冰率領的團隊長期從事雷帕霉素靶蛋白信號通路與腫瘤發(fā)生和治療的研究,。雷帕霉素靶蛋白作為一個細胞內(nèi)承上啟下的蛋白質(zhì)激酶樞紐，主要通過整合生長因子和營養(yǎng)信號來調(diào)節(jié)細胞生長,。多種原癌基因激活,、抑癌基因失活突變后會導致這條信號通路的調(diào)節(jié)失控、過度活化,，從而引起各種疾病,，尤其是腫瘤的發(fā)生。
他們研究發(fā)現(xiàn),，雷帕霉素靶蛋白功能亢進是導致腫瘤細胞發(fā)生“瓦伯格效應”的關鍵因素,，并進一步研究明確了雷帕霉素靶蛋白是通過上調(diào)幾個在腫瘤發(fā)生中起主要作用的蛋白質(zhì)來促進M2型丙酮酸激酶的表達和糖酵解的發(fā)生，聯(lián)合阻斷雷帕霉素靶蛋白通路和糖酵解可協(xié)同抑制腫瘤的發(fā)生和進展,，聯(lián)合抑制這些新發(fā)現(xiàn)的腫瘤藥物靶標可能增加抗腫瘤藥物的療效,、減少副作用和降低腫瘤抗藥性。
mTOR信號途徑是最近新出現(xiàn)的細胞內(nèi)重要信號途徑,，這一途徑在進化上高度保守,，主要通過控制蛋白合成來調(diào)節(jié)細胞生長。mTOR信號通路是調(diào)控細胞生長與增殖的一個關鍵通路,，該通路將從營養(yǎng)分子,、能量狀態(tài)以及生長因子傳來的信號整合在一起，調(diào)控大量的生命過程,，包括自我吞噬,、核糖體的生物組合和代謝等,。該通路的失調(diào)與多種人類疾病相關,，包括癌癥、糖尿病與心血管疾病,。（生物谷Bioon.com）
生物谷推薦原文出處：
PNAS doi: 10.1073/pnas.1014769108
Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth
Qian Suna, Xinxin Chena, Jianhui Mab, Haiyong Penga, Fang Wanga, Xiaojun Zhaa, Yanan Wanga, Yanling Jinga, Hongwang Yanga, Rongrong Chena, Long Changa, Yu Zhangc, June Gotod, Hiroaki Ondae, Tong Chenf, Ming-Rong Wangc, Youyong Lug, Han Youb,1, David Kwiatkowskid, and Hongbing Zhanga,1
Although aerobic glycolysis (the Warburg effect) is a hallmark of cancer, key questions, including when, how, and why cancer cells become highly glycolytic, remain less clear. For a largely unknown regulatory mechanism, a rate-limiting glycolytic enzyme pyruvate kinase M2 (PKM2) isoform is exclusively expressed in embryonic, proliferating, and tumor cells, and plays an essential role in tumor metabolism and growth. Because the receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) signaling cascade is a frequently altered pathway in cancer, we explored its potential role in cancer metabolism. We identified mTOR as a central activator of the Warburg effect by inducing PKM2 and other glycolytic enzymes under normoxic conditions. PKM2 level was augmented in mouse kidney tumors due to deficiency of tuberous sclerosis complex 2 and consequent mTOR activation, and was reduced in human cancer cells by mTOR suppression. mTOR up-regulation of PKM2 expression was through hypoxia-inducible factor 1α (HIF1α)-mediated transcription activation, and c-Myc–heterogeneous nuclear ribonucleoproteins (hnRNPs)-dependent regulation of PKM2 gene splicing. Disruption of PKM2 suppressed oncogenic mTOR-mediated tumorigenesis. Unlike normal cells, mTOR hyperactive cells were more sensitive to inhibition of mTOR or glycolysis. Dual suppression of mTOR and glycolysis synergistically blunted the proliferation and tumor development of mTOR hyperactive cells. Even though aerobic glycolysis is not required for breach of senescence for immortalization and transformation, the frequently deregulated mTOR signaling during multistep oncogenic processes could contribute to the development of the Warburg effect in many cancers. Components of the mTOR/HIF1α/Myc–hnRNPs/PKM2 glycolysis signaling network could be targeted for the treatment of cancer caused by an aberrant RTK/PI3K/AKT/mTOR signaling pathway.
