癌細(xì)胞葡萄糖代謝重編程的分子基礎(chǔ)*

趙世光

癌細(xì)胞葡萄糖代謝重編程的分子基礎(chǔ)*

趙世光

趙世光 教授，主任醫(yī)師，博士生導(dǎo)師，現(xiàn)任哈爾濱醫(yī)科大學(xué)附屬第一醫(yī)院神經(jīng)外科主任，黑龍江省高校神經(jīng)外科重點(diǎn)實驗室主任，國家臨床重點(diǎn)?？平ㄔO(shè)項目負(fù)責(zé)人；兼任中國抗癌協(xié)會神經(jīng)腫瘤專業(yè)委員會主任委員，中國康復(fù)醫(yī)學(xué)會創(chuàng)傷康復(fù)專業(yè)委員會副主任委員，中國神經(jīng)科學(xué)學(xué)會神經(jīng)創(chuàng)傷與修復(fù)分會副主任委員。先后獲得“龍江學(xué)者”、“衛(wèi)生部有突出貢獻(xiàn)中青年專家”等獎項。主要從事膠質(zhì)瘤的分子基礎(chǔ)和臨床研究，其中在熒光引導(dǎo)膠質(zhì)瘤切除術(shù)方面的貢獻(xiàn)受到了國內(nèi)外專家的認(rèn)可，該技術(shù)被寫入中華醫(yī)學(xué)會《中國中樞神經(jīng)系統(tǒng)膠質(zhì)瘤診斷和治療指南》。擔(dān)任《Brain Tumor Pathology》國際編委，《中國神經(jīng)腫瘤雜志》副主編。主持國家級、省級課題20余項，獲教育部、省政府二等獎等成果獎勵20余項。發(fā)表學(xué)術(shù)論文150余篇，其中SCI收錄52篇。應(yīng)邀在國內(nèi)外學(xué)術(shù)會議上做大會報告50余次，12次擔(dān)任國內(nèi)外學(xué)術(shù)會議共同主席。

代謝的重編程是癌細(xì)胞的基本特征之一，其中葡萄糖代謝方式和途徑的改變對癌癥的發(fā)生和發(fā)展至關(guān)重要。即使在氧氣足夠充足的情況下，快速增殖的癌細(xì)胞生長所需的能量主要由糖酵解而非氧化磷酸化提供，癌細(xì)胞這種特殊的糖代謝現(xiàn)象被稱為Warburg效應(yīng)。這種特有的能量獲取方式已在多種癌細(xì)胞中得到驗證，以癌細(xì)胞對葡萄糖高攝取率和利用增加為原理的18F-FDG PET/CT顯像已廣泛應(yīng)用于臨床的癌癥診斷。但癌細(xì)胞為何利用有氧酵解獲取能量以及有氧酵解進(jìn)行的分子基礎(chǔ)目前尚不明確，本文圍繞調(diào)控癌細(xì)胞糖酵解進(jìn)程中的直接調(diào)控酶、癌基因及致癌代謝小分子進(jìn)行分析和綜述。

癌 葡萄糖代謝 Warburg效應(yīng)

近年來，細(xì)胞代謝重編程在癌癥中的重要性受到學(xué)者的廣泛關(guān)注，特別是葡萄糖代謝方式的改變。然而癌細(xì)胞葡萄糖代謝的分子機(jī)制尚不明確。本文在前期研究的基礎(chǔ)上針對癌細(xì)胞糖代謝重編程中的分子機(jī)制進(jìn)行綜述，希望為癌癥的治療提供一定的理論依據(jù)。

1 癌細(xì)胞有氧糖酵解的優(yōu)勢

葡萄糖是細(xì)胞獲取能量的最主要來源。在氧氣充足條件下，正?；蚍只募?xì)胞通過三羧酸循環(huán)（tricarboxylicacidcycle，TCA）將葡萄糖代謝并生成二氧化碳，在氧化磷酸化的過程中，每摩爾葡萄糖產(chǎn)生30或32 moL的三磷酸腺苷（adenosine triphosphate，ATP）和少量乳酸；僅在缺氧條件下，正?；蚍只募?xì)胞才會通過無氧酵解的方式產(chǎn)生大量乳酸。與之截然不同的是，無論在氧氣充足還是缺少的情況下，癌細(xì)胞均會優(yōu)先利用糖酵解的方式產(chǎn)生大量的乳酸，并且每摩爾葡萄糖僅產(chǎn)生2 moL的ATP，有研究［1-2］認(rèn)為這是由于癌細(xì)胞內(nèi)部發(fā)生在線粒體上的氧化磷酸化途徑被永久性破壞所致。但是隨后的多項研究表明線粒體的功能在大多數(shù)癌細(xì)胞內(nèi)并未被破壞，那么癌細(xì)胞因何利用如此低效率的糖代謝方式，目前對此的解釋是癌細(xì)胞高強(qiáng)度的糖酵解對癌細(xì)胞的生長有以下兩種優(yōu)點(diǎn)。1）有氧酵解雖然導(dǎo)致每摩爾葡萄糖產(chǎn)生的ATP量較少，但是卻能夠充分利用細(xì)胞外的營養(yǎng)物質(zhì)和葡萄糖來產(chǎn)生足夠的ATP，這是因為在糖酵解底物充足和循環(huán)效率足夠高的情況下，糖酵解產(chǎn)生的ATP超過氧化磷酸化所產(chǎn)生的ATP［1，3］。2）糖代謝方式的改變?yōu)榧?xì)胞的合成代謝提供豐富的底物，如為核酸合成提供核糖、為脂類合成提供甘油和檸檬酸及大量的非必需氨基酸等［1，4］。這些特點(diǎn)被認(rèn)為是癌細(xì)胞利用有氧糖酵解的原因。

2 癌細(xì)胞有氧糖酵解進(jìn)行的分子基礎(chǔ)

癌細(xì)胞有氧酵解的進(jìn)行依賴多個糖酵解關(guān)鍵限速酶、致癌/抑癌基因及其他多條癌癥相關(guān)通路的調(diào)控。這些基因的位點(diǎn)突變、轉(zhuǎn)錄前/后修飾、異常表達(dá)及繼發(fā)性癌癥相關(guān)通路的激活形成的分子調(diào)控網(wǎng)絡(luò)共同導(dǎo)致并維持了癌細(xì)胞內(nèi)有氧酵解的進(jìn)行、癌細(xì)胞的存活和生長。

2.1 己糖激酶2（hexokinase 2，HK2）

HK2是HK家族的重要成員之一，也是糖酵解第一個關(guān)鍵限速酶。在多種癌組織中HK2的表達(dá)水平均顯著升高，HK2的沉默能有效降低有氧糖酵解的水平，促使癌細(xì)胞的代謝方式由有氧酵解向氧化磷酸化轉(zhuǎn)變［5-7］。目前研究［7-14］顯示HK2的轉(zhuǎn)錄、表達(dá)及其在細(xì)胞內(nèi)的分布與缺氧誘導(dǎo)因子-1α（hypoxia inducible factor-1α，HIF-1α）、AKT活化狀態(tài)、葡萄糖濃度及miR-143的表達(dá)密切相關(guān)。HK2在癌細(xì)胞中的高表達(dá)及其復(fù)雜的調(diào)控網(wǎng)絡(luò)直接促進(jìn)了癌細(xì)胞有氧糖酵解水平的提高，滿足了快速增殖細(xì)胞對能量的需求，進(jìn)而維持癌細(xì)胞在低氧、低糖及酸性微環(huán)境中生存。

2.2 丙酮酸激酶2（pyruvate kinase M2，PKM2）

PKM2是糖酵解調(diào)控的關(guān)鍵限速酶之一。大量研究顯示PKM2在胃癌、腸癌、膠質(zhì)瘤及肺癌等組織中的表達(dá)異常增高，正?；蚍只墒斓募?xì)胞主要表達(dá)PKM1而非PKM2，PKM2的表達(dá)水平與多種癌細(xì)胞的致瘤能力呈正相關(guān)，與癌癥患者的預(yù)后呈負(fù)相關(guān)［15-17］。為保證PKM2的高表達(dá)，癌細(xì)胞內(nèi)選擇性剪切蛋白（hnRNP）可促使糖酵解的限速酶丙酮酸激酶從M1型向M2型轉(zhuǎn)變［18］。有研究［19-20］表明PKM2過表達(dá)能對抗凋亡因子對癌細(xì)胞的殺傷作用，促進(jìn)癌細(xì)胞增殖；PKM2的敲除則抑制癌細(xì)胞的增殖、侵襲以及體內(nèi)癌組織的生長［21］。PKM2在細(xì)胞內(nèi)有二聚體和四聚體兩種存在形式，有研究［22-24］證實二聚體在有氧酵解的發(fā)生過程中扮演重要角色，而四聚體則主要通過TCA循環(huán)為細(xì)胞提供能量，兩者的動態(tài)平衡依賴致癌基因和抑癌基因所組成的復(fù)雜分子網(wǎng)絡(luò)的精細(xì)調(diào)控，共同維持癌細(xì)胞的致瘤能力。

2.3 丙酮酸脫氫酶（pyruvate dehydrogenase，PDH）

PDH是線粒體內(nèi)部氧化磷酸化進(jìn)行的關(guān)鍵調(diào)控因子之一，其可使丙酮酸轉(zhuǎn)化為乙酰輔酶A，PDH的表達(dá)下降間接使癌細(xì)胞內(nèi)的糖酵解增強(qiáng)、乳酸生成增多［4，25-26］。PDH受線粒體基質(zhì)蛋白丙酮酸脫氫酶激酶（pyruvate dehydrogenase kinase，PDK）的調(diào)控，PDK可以通過磷酸化PDH的E1α亞基抑制癌細(xì)胞氧化磷酸化的進(jìn)行［27］。另外，PDH復(fù)合體還受細(xì)胞內(nèi)乙酰輔酶A和NAD/NADH比率的影響［4，28］。DCA是PDK的抑制劑，其具有抑制PDK進(jìn)而增強(qiáng)PDH、降低乳酸外流及促進(jìn)氧化磷酸化的功能。目前研究［29-30］顯示DCA主要通過促進(jìn)線粒體膜的去極化、提高癌細(xì)胞內(nèi)活性氧（reactive oxygen species，ROS）水平及上調(diào)電壓依賴性鉀離子通道等多種途徑導(dǎo)致繼發(fā)性的凋亡途徑激活，進(jìn)而導(dǎo)致癌細(xì)胞凋亡。

3 調(diào)控癌細(xì)胞糖代謝的癌基因和代謝小分子

3.1 HIF-1α

在實體癌組織內(nèi)，細(xì)胞生長在一個缺氧的微環(huán)境中。HIF-1α是細(xì)胞應(yīng)對缺氧的感受器，雖然常氧狀態(tài)下HIF-1α通過與VHL形成的復(fù)合體依賴泛素化的途徑很快被降解，但是缺氧能夠通過激活ROS抑制泛素化的調(diào)控作用，促使HIF-1α穩(wěn)定及其在細(xì)胞內(nèi)的累積［31-32］。HIF-1α蛋白的異常堆積能夠顯著降低氧化磷酸化的效率，這在一定程度上促使癌細(xì)胞轉(zhuǎn)向利用糖酵解來獲取能量維持自身的生存；糖酵解會產(chǎn)生大量的乳酸、丙酮酸等代謝產(chǎn)物，這些代謝分子在細(xì)胞內(nèi)積聚，進(jìn)一步促使HIF-1α表達(dá)及活性的增加，最終形成了缺氧促進(jìn)癌細(xì)胞糖酵解和大量乳酸的產(chǎn)生，乳酸反過來促進(jìn)HIF-1α表達(dá)及活性增加的惡性循環(huán)［33-34］。HIF-1α對癌細(xì)胞此種糖酵解的影響主要依賴于其對糖代謝過程中酶的調(diào)控。有研究［35-39］證實HIF-1α作為重要的轉(zhuǎn)錄因子對參與葡萄糖轉(zhuǎn)運(yùn)的膜受體GLUT1及GLUT3，己糖激酶（HK）、葡萄糖-6-磷酸脫氫酶（G6PD）、乳酸脫氫酶A（LDHA）和單羧酸轉(zhuǎn)運(yùn)蛋白4（MCT4）等的表達(dá)均有重要影響。雖然上述證據(jù)表明HIF-1α對癌細(xì)胞的糖酵解進(jìn)行及維持缺氧狀態(tài)下的細(xì)胞存活至關(guān)重要，但是也有學(xué)者［40-42］指出HIF-1α通過調(diào)控PDK1和PDH酶的表達(dá)或活性使糖酵解產(chǎn)物丙酮酸進(jìn)入三羧酸循環(huán)的數(shù)量顯著減少，該過程顯著減少癌細(xì)胞生長和增殖所需要的用于細(xì)胞內(nèi)生物合成的中間產(chǎn)物產(chǎn)生。除了缺氧可以激活HIF-1α之外，一些生長因子比如胰島素樣-1（IGF-1）、EGF也可以激活HIF系統(tǒng)，刺激并促進(jìn)癌細(xì)胞生長，一定程度上彌補(bǔ)由于缺氧所導(dǎo)致的生物合成過程中中間產(chǎn)物的缺乏，這些證據(jù)是對HIF-1α調(diào)控癌細(xì)胞糖酵解的重要補(bǔ)充［43-44］。

3.2 p53

p53是對抗癌細(xì)胞生長的重要保護(hù)蛋白，能夠抑制多種致癌因素驅(qū)動下的癌細(xì)胞增殖、生長并促進(jìn)其凋亡。越來越多的證據(jù)表明p53通過多種方式調(diào)控癌細(xì)胞的代謝進(jìn)而影響癌細(xì)胞的生物學(xué)行為。糖酵解是癌細(xì)胞獲取能量的主要來源，TP53誘導(dǎo)的糖酵解和凋亡調(diào)節(jié)因子（TP53-induced glycolysis and apoptosis regulator，TIGAR）能夠改變癌細(xì)胞對葡萄糖利用的多條通路，增強(qiáng)磷酸戊糖途徑，致使細(xì)胞內(nèi)還原型煙酰胺腺嘌呤二核苷酸磷酸（nicotinamide-adenine dinucleotide phosphate，NADPH）的積聚，進(jìn)而對抗癌細(xì)胞內(nèi)部的ROS，促進(jìn)癌細(xì)胞存活；由于TIGAR啟動子上有兩個可以結(jié)合p53的位點(diǎn)，因此p53能夠靶向結(jié)合TIGAR，抑制其轉(zhuǎn)錄進(jìn)而降低癌細(xì)胞的糖酵解，抑制癌細(xì)胞生長［45-47］。除了抑制糖酵解之外，p53也能提高癌細(xì)胞氧化磷酸化的能力，研究證實p53直接結(jié)合致SCO2的啟動子，促進(jìn)該蛋白的轉(zhuǎn)錄及合成，SCO2主要的功能在于將銅離子轉(zhuǎn)移致Cox復(fù)合體上，是細(xì)胞線粒體氧化磷酸化進(jìn)行的重要調(diào)控因子之一，在癌細(xì)胞內(nèi)過表達(dá)SCO2增加氧化磷酸化的水平，p53缺乏的細(xì)胞內(nèi)SCO2蛋白表達(dá)及氧化磷酸化水平均顯著降低，而糖酵解的水平卻明顯增強(qiáng)［47-48］。以上研究結(jié)果提示p53的缺失或突變導(dǎo)致的SCO2蛋白表達(dá)降低破壞了氧化磷酸化的呼吸鏈，最終導(dǎo)致細(xì)胞所需ATP的產(chǎn)生由氧化磷酸化向有氧酵解轉(zhuǎn)變。綜上所述，這些證據(jù)表明p53的激活通過抑制糖酵解，促進(jìn)線粒體內(nèi)的氧化磷酸化調(diào)控癌細(xì)胞的糖代謝；然而p53如何通過復(fù)雜的分子調(diào)控網(wǎng)絡(luò)同時協(xié)調(diào)這兩個方面的功能有待進(jìn)一步研究。

3.3 c-Myc

c-Myc的表達(dá)增強(qiáng)在腸癌、乳腺癌、前列腺癌和膀胱癌等惡性腫瘤中均比較常見，c-Myc蛋白對癌細(xì)胞的作用主要依賴其作為轉(zhuǎn)錄因子調(diào)控細(xì)胞周期的作用。隨著學(xué)者們對該蛋白認(rèn)識的不斷深入，越來越多的證據(jù)提示c-Myc與癌細(xì)胞的糖代謝進(jìn)程密切相關(guān)，其中c-Myc調(diào)控LDHA的證據(jù)被最先發(fā)現(xiàn)［49］，然后c-Myc刺激GLUT1的表達(dá)，促進(jìn)葡萄糖向細(xì)胞內(nèi)的轉(zhuǎn)運(yùn)，c-Myc誘導(dǎo)HK2、PKM2等糖酵解關(guān)鍵酶在癌細(xì)胞內(nèi)的表達(dá)并加速糖酵解的作用被陸續(xù)發(fā)現(xiàn)［50-52］。這些研究結(jié)果提示c-Myc通過促進(jìn)糖酵解的各個環(huán)節(jié)，加快乳酸和ATP的生成，增強(qiáng)癌細(xì)胞的致瘤能力。研究還發(fā)現(xiàn)c-Myc除了直接對糖酵解代謝途徑產(chǎn)生影響之外，還通過調(diào)控miR-23a/miR-23b間接調(diào)控GLS，后者是谷氨酰胺轉(zhuǎn)化為谷氨酸的第一個酶，使得癌細(xì)胞內(nèi)部有充足的谷氨酸轉(zhuǎn)化為α-酮戊二酸進(jìn)入TCA循環(huán)，因此c-Myc高表達(dá)的細(xì)胞對谷氨酰胺的需求增加，而谷氨酰胺的剝奪顯著減少了三羧酸循環(huán)的中間代謝產(chǎn)物并誘導(dǎo)癌細(xì)胞的凋亡，癌細(xì)胞對谷氨酰胺的這種高度依賴被認(rèn)為與c-Myc活性顯著相關(guān)［53］。另外，有研究顯示缺氧誘導(dǎo)因子HIF-1與c-Myc具有協(xié)同促進(jìn)糖酵解關(guān)鍵酶表達(dá)的作用，兩者分別在缺氧和常氧條件下調(diào)控糖酵解酶的表達(dá)，促進(jìn)癌細(xì)胞在缺氧環(huán)境中生存及癌組織的生長［54-55］。

3.4 代謝分子2-羥基戊二酸（2-hydroxyglutarate，2-HG）的致癌作用

異檸檬酸脫氫酶1（isocitrate dehydrogenase 1，IDH1）的突變在癌細(xì)胞中普遍存在，該突變在癌癥進(jìn)展的早期階段扮演重要角色，IDH1的突變導(dǎo)致異檸檬酸向酮戊二酸轉(zhuǎn)化的能力減弱進(jìn)而使2-HG在細(xì)胞內(nèi)的聚集增加［56-57］。在正常細(xì)胞中2-HG是三羧酸循環(huán)的副產(chǎn)物，表達(dá)水平較低，一般不具有生物學(xué)功能，但在癌組織中2-HG通過競爭性抑制的機(jī)制參與對惡性腫瘤細(xì)胞生物學(xué)行為的調(diào)控，主要表現(xiàn)為2-HG的累積可以抑制包括人體內(nèi)“組蛋白去甲基化酶”與“脯氨酸羥化酶”在內(nèi)的多個重要雙加氧酶的活力，從而改變細(xì)胞的增殖和生長方式，防止HIF-1的泛素化降解，促進(jìn)HIF-1積聚，維持癌細(xì)胞在低氧環(huán)境下的生存，促進(jìn)正常細(xì)胞向癌細(xì)胞的轉(zhuǎn)化進(jìn)并誘發(fā)惡性腫瘤［58-59］。2-HG還可通過調(diào)控組蛋白H3K9和H3K27的甲基化抑制癌細(xì)胞的分化［60］。

4 總結(jié)和展望

癌細(xì)胞糖代謝方式的改變不是由單一的基因異常造成，而是多基因、多通路共同作用使細(xì)胞內(nèi)部多個生物代謝化學(xué)反應(yīng)通路繼發(fā)性減弱或增強(qiáng)的結(jié)果，其目的是為了滿足癌細(xì)胞對營養(yǎng)物質(zhì)和能量的需求，維持自身的存活和增殖。然而目前對癌細(xì)胞代謝重編程的分子機(jī)制研究仍然處于初級階段，隨著組學(xué)技術(shù)特別是代謝組學(xué)技術(shù)在癌領(lǐng)域的利用和快速發(fā)展，相信更多癌代謝相關(guān)的通路和分子會被發(fā)現(xiàn)，針對癌代謝的分子靶向治療也將成為未來研究的熱點(diǎn)。

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（2014-03-31收稿）

（2014-04-30修回）

Molecular basis of glucose metabolic reprogramming in cancer cells

Shiguang ZHAO;E-mail:guangsz@hotmail.com
Department of Neurosurgery,The FirstAffiliated Hospital of Harbin Medical University,Harbin 150001,China

Cancer metabolic reprogramming is among the basic characteristics of cancer cells.Changes in glucose metabolism are essential for carcinogenesis and cancer development.Previous study indicated that energy is acquired mainly via glycolysis rather than oxidative phosphorylation in the presence of sufficient oxygen levels to promote the rapid proliferation of cells,such as cancer cells.This phenomenon is called the"Warburg effect."Furthermore,this unique approach of energy production in cancer cells has been validated in various types of cancer cells.On the basis of the characteristics of cancer cells with high glucose uptake and utilization,clinicians and medical practitioners extensively apply 18-fludeoxyglucose positron emission tomography in clinical diagnosis.Tumor cells undergo aerobic glycolysis to produce energy,but this metabolic pathway is poorly efficient;the molecular basis of aerobic glycolysis and the reason for these cells to undergo this metabolic pathway also remain unclear.In this article,glycolysis-related processes,including enzyme,oncogene,and oncometabolite regulation,in cancer cells are summarized.

cancer,glucose metabolism,Warburg effect

10.3969/j.issn.1000-8179.20140513

哈爾濱醫(yī)科大學(xué)附屬第一醫(yī)院神經(jīng)外科（哈爾濱市150001）

*本文課題受國家自然科學(xué)基金項目（編號：81272788）資助

趙世光 guangsz@hotmail.com

Shiguang ZHAO

This study was supported by the National Natural Science Foundation of China(No.81272788)

邢穎）