管明秀，管明華，張穎超，周云麗，鄭大勇，王寶占天津醫(yī)科大學(xué)寶坻臨床學(xué)院//天津市寶坻區(qū)人民醫(yī)院檢驗(yàn)科，天津 0800；天津醫(yī)科大學(xué)附屬腫瘤醫(yī)院乳腺外科；檢驗(yàn)科，天津 00060

M2型丙酮酸激酶在腫瘤細(xì)胞中的多功能性

管明秀1，管明華2，張穎超1，周云麗3，鄭大勇1，王寶占1
1天津醫(yī)科大學(xué)寶坻臨床學(xué)院//天津市寶坻區(qū)人民醫(yī)院檢驗(yàn)科，天津 301800；2天津醫(yī)科大學(xué)附屬腫瘤醫(yī)院乳腺外科；3檢驗(yàn)科，天津 300060

丙酮酸激酶是葡萄糖代謝的關(guān)鍵限速酶。它主要有4種同工酶形式，L型、R型、M1型和M2型。M2型丙酮酸激酶主要表達(dá)于腫瘤細(xì)胞當(dāng)中。腫瘤細(xì)胞對(duì)葡萄糖的代謝主要是通過有氧糖酵解的形式來完成，這一過程中M2型丙酮酸激酶起著關(guān)鍵限速酶的作用，同時(shí)在腫瘤細(xì)胞增殖過程中也起著調(diào)控信號(hào)轉(zhuǎn)導(dǎo)的作用。M2型丙酮酸激酶為腫瘤細(xì)胞的增殖提供了能源和物質(zhì)基礎(chǔ)，它可以作為早期檢測(cè)腫瘤的生物標(biāo)記物。深入了解M2型丙酮酸激酶在腫瘤中的作用及機(jī)制可以為腫瘤靶向治療提供新的思路。

M2型丙酮酸激酶；腫瘤；糖酵解；非糖酵解

細(xì)胞生存的關(guān)鍵因素是獲得充足的能量供應(yīng)。腫瘤細(xì)胞在低氧條件下利用糖酵解產(chǎn)能供給細(xì)胞生存，這種現(xiàn)象稱為Warburg效應(yīng)[1]。有研究證實(shí)M2型丙酮酸激酶（PKM2）是糖酵解的關(guān)鍵調(diào)節(jié)酶，為細(xì)胞增殖提供了核酸、氨基酸、脂類等物質(zhì)基礎(chǔ)[2]。除了具有糖酵解功能，PKM2的非糖酵解功能也引起了廣泛的關(guān)注。本文主要描述PKM2在腫瘤細(xì)胞中的功能，以及探討其潛在的治療應(yīng)用價(jià)值。

1 丙酮酸激酶的4個(gè)亞型

丙酮酸激酶是糖酵解酶，它可以催化磷酸烯醇式丙酮酸和ADP產(chǎn)生丙酮酸和ATP。丙酮酸激酶有4種亞型（PKL、PKR、PKM1和PKM2）。L型和R型被PKLR基因編碼，它們的表達(dá)具有組織特異性。L型主要表達(dá)在肝、腎和腸組織中；R型主要表達(dá)在紅細(xì)胞中[3]。PKM1和PKM2被PKM基因編碼，是mRNA不同剪切體的產(chǎn)物，PKM1是外顯子9，主要表達(dá)在成人的分化組織中，如腦組織和肌肉組織[4-5]；PKM2是外顯子10，主要表達(dá)在胚胎細(xì)胞、成人干細(xì)胞和腫瘤細(xì)胞中[6-7]。

2 PKM2在腫瘤細(xì)胞中的表達(dá)

除了胚胎細(xì)胞和成人干細(xì)胞，PKM2是腫瘤細(xì)胞中主要的存在形式[8-9]。PKM2的表達(dá)在腫瘤生長過程中起著重要的作用[10-11]。近年來，有研究發(fā)現(xiàn)了PKM2表達(dá)的調(diào)節(jié)因子mTOR，mTOR的激活導(dǎo)致PKM2表達(dá)的增加，從而反轉(zhuǎn)錄激活低氧誘導(dǎo)因子（HIF-1），進(jìn)而促進(jìn)了腫瘤的發(fā)生。因此，PKM2是早期檢測(cè)腫瘤的生物標(biāo)志物。

3 PKM2的糖酵解功能

Warburg效應(yīng)中PKM2是以低活性的酶形式存在的，這為腫瘤的發(fā)生發(fā)展提供了有利的條件。首先糖酵解途徑產(chǎn)能的速度比氧化磷酸化途徑更快[12]，同時(shí)可以使含碳有機(jī)物更快速合成，從而為腫瘤細(xì)胞的發(fā)生發(fā)展提供大量的物質(zhì)基礎(chǔ)[13]。有研究證實(shí)，通過大量葡萄糖的消耗糖酵解能以較快的速度產(chǎn)生ATP，但是產(chǎn)生ATP的量是比較低的[14]。其次低活性PKM2促進(jìn)了糖酵解中間代謝產(chǎn)物核酸等的生成和堆積，這為腫瘤細(xì)胞的發(fā)展提供了物質(zhì)基礎(chǔ)[15-16]。總之，低活性PKM2促進(jìn)了糖酵解，從而為腫瘤細(xì)胞增殖提供了各種資源，比如能量和物質(zhì)。

PKM2有3種活性形式：無活性的單體，低活性的二聚體和高活性的四聚體，而PKM1主要以高活性四聚體形式存在[17]。腫瘤細(xì)胞PKM2主要以低活性的二聚體形式存在[18]，而正常的增殖細(xì)胞則以高活性的四聚體形式存在[8]。有研究報(bào)道PKM1表達(dá)的細(xì)胞中比PKM2表達(dá)的細(xì)胞中丙酮酸激酶的活性要高，這些細(xì)胞消耗的氧量更多，產(chǎn)生的乳酸少，對(duì)于線粒體ATP生成抑制劑寡霉素更加敏感[19-20]。腫瘤細(xì)胞中PKM2的絲氨酸和酪氨酸位點(diǎn)會(huì)發(fā)生磷酸化，PKM2上的磷酸酪氨酸能夠促進(jìn)1,6-二磷酸果糖從PKM2的結(jié)合口袋上釋放出來，使得四聚體轉(zhuǎn)變?yōu)闊o活性的二聚體，從而使糖酵解向生物合成轉(zhuǎn)變[21]。使細(xì)胞有氧糖酵解能力增加，加快腫瘤的發(fā)展。E7蛋白是人乳頭瘤病毒16型中的癌蛋白，和PKM2結(jié)合以后能加劇PKM2二聚化，加快腫瘤發(fā)展。

有研究報(bào)道，有多種因子可以調(diào)節(jié)PKM2二聚體和四聚體形式的轉(zhuǎn)換[22-24]。例如，糖酵解中間代謝產(chǎn)物1,6-二磷酸果糖可以對(duì)PKM2進(jìn)行變構(gòu)調(diào)節(jié)。二聚體形式的PKM2可以被1,6-二磷酸果糖變構(gòu)調(diào)節(jié)生成四聚體。PKM2上的磷酸酪氨酸能夠促進(jìn)1,6-二磷酸果糖從PKM2的結(jié)合口袋上釋放出來，使得四聚體轉(zhuǎn)變?yōu)闊o活性的二聚體，從而使糖酵解向生物合成轉(zhuǎn)變。四聚體的PK與細(xì)胞的高ATP:ADP及GTP:GDP的比值有關(guān)，二聚體形式的則相反。絲氨酸產(chǎn)生于糖酵解中間代謝產(chǎn)物3-磷酸甘油酸，它也是PKM2的調(diào)節(jié)因子[25]。除此之外，癌基因蛋白HPV-16 E7和有活性的pp60V-Src結(jié)合四聚體形式的PKM2后會(huì)產(chǎn)生二聚體形式的PKM2[8]。近年來研究發(fā)現(xiàn)高氧環(huán)境下會(huì)引起PKM2四聚體形式的解離，從而降低了PKM2的活性[26-27]，并且PKM2賴氨酸殘基乙?；种屏薖KM2酶活性，從而通過伴侶介導(dǎo)的自噬導(dǎo)致了降解[28]。

4 PKM2的非糖酵解功能

PKM2可以和很多分子相互作用[29-31]，其中有些分子影響了PKM2的糖酵解功能，這些分子直接調(diào)控Warburg效應(yīng)。大量研究報(bào)道了PKM2的非糖酵解功能，特別是PKM2在轉(zhuǎn)錄中的作用引起了廣泛的關(guān)注，有研究報(bào)道PKM2可以和HIF-1直接相互作用，從而促進(jìn)HIF-1靶基因的轉(zhuǎn)錄激活[32]。也有很多研究報(bào)道了PKM2的核易位。白細(xì)胞介素-3和表皮生長因子受體激活，可以導(dǎo)致PKM2核易位的發(fā)生，從而激活基因轉(zhuǎn)錄和細(xì)胞增殖[33]。當(dāng)細(xì)胞受到生長因子信號(hào)刺激時(shí)，PKM2活性受到抑制，加強(qiáng)糖酵解途徑，導(dǎo)致葡萄糖代謝產(chǎn)物積累，為細(xì)胞增殖提供能量和物質(zhì)基礎(chǔ)。美國德克薩斯大學(xué)一研究團(tuán)隊(duì)也揭示PKM2可通過一種非代謝機(jī)制促進(jìn)細(xì)胞增殖和腫瘤形成[34]，該研究證實(shí)，PKM2對(duì)表皮生長因子受體是十分重要的，提升β連環(huán)蛋白活性，從而引起基因表達(dá)、細(xì)胞生長及腫瘤的形成。該研究證實(shí)在人類癌細(xì)胞中表皮生長因子受體信號(hào)活化可誘導(dǎo)PKM2易位進(jìn)入細(xì)胞核，在細(xì)胞核中PKM2的K433與β-catenin的c-Src磷酸化Y333位點(diǎn)結(jié)合，進(jìn)而調(diào)控Cyclin D1表達(dá)，從而導(dǎo)致細(xì)胞增殖速度加快以及腫瘤的形成。

細(xì)胞核中的PKM2主要以二聚體的形式存在，然而細(xì)胞質(zhì)中的PKM2以二聚體和四聚體兩種形式存在[35]。除此以外，細(xì)胞核中的PKM2發(fā)揮著蛋白激酶的作用，它可以使Stat3磷酸化進(jìn)而激活腫瘤相關(guān)基因的轉(zhuǎn)錄，比如Mek5[36]。綜合這些研究可推斷PKM2在促進(jìn)腫瘤細(xì)胞發(fā)生發(fā)展過程中具有兩方面的作用：首先，細(xì)胞質(zhì)中二聚體形式的PKM2作為丙酮酸激酶發(fā)揮作用，低活性的PKM2維持了細(xì)胞的糖酵解過程，并且促進(jìn)了糖酵解中間代謝產(chǎn)物的生成，為腫瘤細(xì)胞的增殖提供物質(zhì)基礎(chǔ)；其次，細(xì)胞質(zhì)中二聚體形式的PKM2易位入核后在細(xì)胞核中起著蛋白激酶的作用。它可以磷酸化特殊的細(xì)胞核蛋白，進(jìn)而促進(jìn)基因轉(zhuǎn)錄，從而使腫瘤細(xì)胞增殖。近年來研究發(fā)現(xiàn)，PKM2在各種環(huán)境條件下具有不同的功能，PKM2與免疫反應(yīng)、基因組不穩(wěn)定性、血管再生、發(fā)病機(jī)制等相關(guān)[37]，這些疾病的發(fā)生是否與PKM2的糖酵解功能和非糖酵解功能相關(guān)需要進(jìn)一步確定。

5 PKM2作為腫瘤治療靶點(diǎn)的前景

PKM2在腫瘤細(xì)胞代謝和信號(hào)轉(zhuǎn)導(dǎo)中起著很多重要的作用，PKM2被認(rèn)為是腫瘤疾病治療的理想靶點(diǎn)。RNA干擾和肽適體可以消融PKM2，并產(chǎn)生破壞腫瘤生長、誘導(dǎo)細(xì)胞凋亡、增加化療藥物敏感性等抗腫瘤效果[38]。PKM2的小分子抑制劑可以抑制糖酵解并引起細(xì)胞死亡。但是PKM2的靶向治療到目前為止還是難點(diǎn)，一是PKM2除了在腫瘤組織中表達(dá)，它在正常增殖組織中也有表達(dá)，二是通過小干擾RNA對(duì)PKM2進(jìn)行基因沉默不能完全抑制腫瘤細(xì)胞增殖。因此激活PKM2催化活性的復(fù)合物可能會(huì)作為腫瘤治療的一個(gè)方式[39]。PKM2在正常組織中是以高活性形式存在的，而在腫瘤組織中則是以低活性形式存在。激活劑可以抑制腫瘤細(xì)胞糖酵解和細(xì)胞增殖，PKM2激活劑與1，6-二磷酸果糖都可以誘導(dǎo)PKM2四聚體形式形成。由于核PKM2是以二聚體形式存在的，PKM2激活劑能夠阻止PKM2從細(xì)胞質(zhì)進(jìn)入細(xì)胞核，從而抑制了核PKM2的功能。換言之，PKM2激活劑可能會(huì)抑制PKM2糖酵解功能和非糖酵解功能。PKM2糖酵解功能抑制劑可以抑制腫瘤細(xì)胞糖酵解，導(dǎo)致了ROS生成量增加以及腫瘤細(xì)胞快速生長所需能源物質(zhì)供應(yīng)量的降低。PKM2非糖酵解功能抑制劑可以抑制腫瘤相關(guān)基因，如Mek5，c-Myc，和各種HIF-1靶基因的活性。它們?cè)谀[瘤治療過程中的合理性需要進(jìn)一步研究證實(shí)。

6 展望

PKM2的糖酵解功能和非糖酵解功能為腫瘤細(xì)胞的生長和生存提供了條件。在早期腫瘤形成過程中就有PKM2的表達(dá)，并且在腫瘤病人的血液和糞便中可以檢測(cè)到[19]；進(jìn)一步研究表明PKM2水平與腫瘤大小和腫瘤分期有關(guān)。

微環(huán)境可以引起腫瘤組織的代謝異質(zhì)性，代謝異質(zhì)性可能由每個(gè)腫瘤細(xì)胞不同的能源物質(zhì)供給以及氧供給有關(guān)，這是由每個(gè)腫瘤細(xì)胞的定植部位離血管的距離不同造成的。PKM2通過糖酵解功能和非糖酵解功能為腫瘤細(xì)胞惡性表型的形成提供了條件，說明PKM2可能會(huì)成為腫瘤治療的一個(gè)有效靶點(diǎn)。然而PKM2具有多面性，它在細(xì)胞內(nèi)發(fā)揮的作用很多很復(fù)雜，而且以PKM2作為靶點(diǎn)進(jìn)行腫瘤治療時(shí)，在正常細(xì)胞產(chǎn)生的效果也很難評(píng)估。因此，在PKM2激活劑和抑制劑被用作干預(yù)治療之前，需要進(jìn)一步研究。

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Versatility of pyruvate kinase M2 in tumor cells

GUAN Mingxiu1, GUAN Minghua2, ZHANG Yingchao1, ZHOU Yunli3, ZHENG Dayong1, WANG Baozhan11Department of Clinical Laboratory, Tianjin Baodi Hospital Affiliated to Tianjin Medical University, Tianjin 301800, China;2Department of Breast Surgery;3Department of Clinical Laboratory, Affiliated Cancer Hospital of Tianjin Medical University, Tianjin 300060,China

Pyruvate kinase is a critical rate limiting enzyme in glucose metabolism. It has mainly 4 isozyme forms: L type, R type, M1 type and M2 type. Pyruvate kinase M2 (PKM2) mainly expressed in tumor cells. The metabolism of glucose by tumor cells is mainly accomplished by aerobic glycolysis. During the process, PKM2 plays a key role in the rate limiting enzyme. It regulates the signal transduction in the process of tumor cell proliferation. Pyruvate kinase M2 provides energy and material basis for the proliferation of tumor cells. It can be used as a biomarker for early detection of tumor. The exploration of mechanism of PKM2 in tumor can provide a new way to tumor targeted treatment.

M2 type pyruvate kinase; tumor; glycolysis; non glycolysis

2017-03-05

管明秀，碩士，主管技師，E-mail：xiusong2007@126.com

王寶占，主管技師，E-mail：baozhanwang66@163.com