腫瘤中M2型丙酮酸激酶的表達(dá)、功能及調(diào)節(jié)

時蒙昆(綜述) 楊曉冬 孫奉昊 詹 成(審校) 時 雨 王 群

(復(fù)旦大學(xué)附屬中山醫(yī)院胸外科 上海 200032)

腫瘤中M2型丙酮酸激酶的表達(dá)、功能及調(diào)節(jié)

時蒙昆(綜述) 楊曉冬 孫奉昊 詹 成△(審校) 時 雨 王 群

(復(fù)旦大學(xué)附屬中山醫(yī)院胸外科 上海 200032)

高水平的糖酵解是癌細(xì)胞的重要特征之一,而其中一個重要的調(diào)節(jié)因子即M2型丙酮酸激酶(M2 type of pyruvate kinase,PKM2)。除此之外,PKM2還具有調(diào)控基因轉(zhuǎn)錄以及細(xì)胞周期進(jìn)展、促進(jìn)腫瘤形成和侵襲遷移等蛋白激酶活性。同時,PKM2受多種轉(zhuǎn)錄因子、癌基因蛋白和中間代謝產(chǎn)物等復(fù)雜因素的調(diào)控。大量研究表明,PKM2在腫瘤的發(fā)生進(jìn)展過程中起著至關(guān)重要的作用,針對PKM2展開相應(yīng)臨床診斷和治療研究有著良好的應(yīng)用前景。

M2型丙酮酸激酶; 腫瘤代謝; 轉(zhuǎn)錄水平

丙酮酸激酶(pyruvate kinase,PK)催化磷酸烯醇式丙酮酸(phosphoenolpyruvate,PEP)與ADP反應(yīng)生成丙酮酸和ATP,是糖酵解的關(guān)鍵酶之一。目前研究表明,M2型丙酮酸激酶(M2 type of pyruvate kinase,PKM2)作為PK的亞型之一,在腫瘤的形成發(fā)展中起著重要的作用。本文就PKM2在腫瘤中的表達(dá)、功能及調(diào)節(jié)進(jìn)行綜述。

PKM2在腫瘤中的表達(dá) 人體內(nèi)存在PKM和PKLR兩種PK的同工酶,而PKM2由PKM基因選擇性剪接而來。通過不同的剪接方式,PKM基因有著多個不同的轉(zhuǎn)錄本和蛋白質(zhì)亞型。目前NCBI和UCSC數(shù)據(jù)庫中共記錄有PKM基因的14個轉(zhuǎn)錄本和12種蛋白質(zhì)亞型,具體信息如圖1[1]:較寬處代表外顯子、較窄處代表內(nèi)含子。深色部分代表翻譯起始密碼子與終止密碼子之間的序列,淺色部分代表5′UTR和3′UTR區(qū)。AA:氨基酸殘基數(shù)量。

圖1 PKM基因的轉(zhuǎn)錄本和蛋白質(zhì)亞型Fig 1 Expression patterns of the transcript rariants of PKM

由圖1可見PKM基因不同亞型序列間存在一定的差別,其中關(guān)于PKM1和PKM2亞型的研究較多,PKM1表達(dá)第12外顯子而PKM2表達(dá)第13外顯子,二者蛋白序列間僅有23個氨基酸殘基存在差異,關(guān)于PKM其他蛋白亞型的研究較少,功能尚不確定。

以往的觀點認(rèn)為,在PKM不同蛋白質(zhì)亞型中,PKM1在正常組織中占據(jù)主導(dǎo)地位,而PKM2在增殖旺盛的組織中高表達(dá),例如胚胎干細(xì)胞、癌細(xì)胞等,胚胎發(fā)育的過程中PKM2逐漸被PKM1取代,隨著正常組織癌變,PKM1又逐步被PKM2所取代[2]。

但近期多項研究指出,在所有正常和腫瘤組織中,PKM2均為主導(dǎo)亞型,并且PKM2在腫瘤組織中較正常組織細(xì)胞顯著增高。Bluemlein等[3]采用質(zhì)譜的方法定量檢測PKM1和PKM2蛋白質(zhì)水平,結(jié)果發(fā)現(xiàn)PKM2在多種正常組織腫瘤組織樣本以及細(xì)胞系樣本中均占二者總量的50%以上,在絕大部分樣本中比例甚至超過95%。我們通過對TCGA數(shù)據(jù)庫中25種腫瘤近8 000例樣本中PKM各亞型相應(yīng)的轉(zhuǎn)錄表達(dá)數(shù)據(jù)進(jìn)行分析,在不同組織類型中PKM2占PKM各亞型總和的57.2%～89.2%,均占絕對主導(dǎo)地位。

傳統(tǒng)觀點認(rèn)為PKM1在腫瘤組織細(xì)胞中含量明顯下降,并且PKM1到PKM2的亞型轉(zhuǎn)換是癌細(xì)胞中PKM2表達(dá)升高的主要原因。Bluemlein等[3]研究認(rèn)為PKM1的表達(dá)在腫瘤中并無顯著變化。而我們的研究發(fā)現(xiàn),雖然PKM總體表達(dá)在腫瘤中顯著性的上升,但PKM1相應(yīng)轉(zhuǎn)錄本的表達(dá)在腫瘤組織細(xì)胞中不升反降,其占PKM總體的比例更是顯著下降,考慮到傳統(tǒng)研究中主要采取免疫組化、Western blot等相對定量的方法來研究PKM1和PKM2的表達(dá)特點,而這些基于抗原抗體反應(yīng)的方法難以對PKM1和PKM2進(jìn)行精確定量,研究受抗原抗體結(jié)合能力影響較大[1]。因此,我們認(rèn)為傳統(tǒng)研究結(jié)果中PKM1在腫瘤中的顯著下降是確定存在的,并與我們的研究結(jié)果相一致。另外,我們的研究發(fā)現(xiàn),PKM2上升幅度遠(yuǎn)高于PKM1下降幅度,但與PKM整體上升幅度相一致,PKM2所占比例并無明顯變化,綜合PKM各亞型相應(yīng)轉(zhuǎn)錄本的表達(dá)變化,我們認(rèn)為PKM2上升主要是因為PKM整體表達(dá)上升所引起的,而非PKM1亞型的轉(zhuǎn)換[1]。在Desai等[4]的研究中,作者混淆了 PKM的不同亞型,因此實驗結(jié)果值得進(jìn)一步商榷。

PKM2在腫瘤代謝中的功能 PKM2存在四聚體和二聚體兩種形式,在腫瘤細(xì)胞中主要以低活性的二聚體存在,在此種情況下,能量代謝被抑制,糖酵解中間代謝產(chǎn)物在細(xì)胞中積累,并參與合成代謝,從而促進(jìn)癌細(xì)胞的快速增殖。因此,在PKM2 占主導(dǎo)作用的癌細(xì)胞內(nèi),PKM2 高活性與低活性之間的比值決定了葡萄糖是用來產(chǎn)生能量還是合成代謝的前體[5]。

癌細(xì)胞在代謝過程中會產(chǎn)生一系列活性氧簇(reactive oxygen species,ROS),ROS通過細(xì)胞氧化應(yīng)激反應(yīng)誘導(dǎo)細(xì)胞凋亡并導(dǎo)致其壞死。Anastasiou等[6]研究發(fā)現(xiàn)PKM2可參與對抗氧化應(yīng)激。首先,PKM2自身結(jié)構(gòu)中含有具有還原活性的半胱氨酸殘基,易與ROS發(fā)生反應(yīng),降低后者在胞內(nèi)的濃度;同時ROS誘導(dǎo)PKM2鈍化使得大量葡萄糖進(jìn)入磷酸戊糖途徑產(chǎn)生還原型輔酶II,還原型輔酶II作為谷胱甘肽(GSH)還原酶的輔酶,可用于維持GSH的還原狀態(tài),對于維持細(xì)胞還原性GSH含量和功能起重要作用。

谷氨酸代謝作為糖代謝受損的代償方式會在癌細(xì)胞糖代謝受損的情況下發(fā)揮作用,PKM2作為重要的調(diào)節(jié)因子參與此過程。Wu等[7]研究結(jié)腸癌細(xì)胞代謝的過程中發(fā)現(xiàn)敲除癌細(xì)胞PKM2基因后細(xì)胞內(nèi)谷氨酰胺酶、運載蛋白表達(dá)增多,進(jìn)一步研究發(fā)現(xiàn)PKM2通過miR-200a對β-catenin/c-myc信號通路有負(fù)性調(diào)控作用,PKM2減少使得β-catenin/c-myc信號通路激活,促進(jìn)谷氨酸代謝以維持癌細(xì)胞增殖。

PKM2在腫瘤分子調(diào)控中發(fā)揮的作用 近年來多項研究發(fā)現(xiàn),PKM2除了在細(xì)胞質(zhì)內(nèi)發(fā)揮作用外,還可以通過多種方式進(jìn)入細(xì)胞核。PKM2在細(xì)胞質(zhì)和細(xì)胞核內(nèi)可以發(fā)揮蛋白激酶的作用,從PEP上轉(zhuǎn)移磷酸基團(tuán)磷酸化多個重要因子并參與腫瘤細(xì)胞的分子調(diào)控(表1)。

表1 PKM2在腫瘤發(fā)生中的調(diào)控作用Tab 1 The role of PKM2 during tumorigenesis

EGFR:Epidermal growth factor receptor;SAICAR:Succinylaminoimidazole carboxamide riboside;C/EBPβ:CCAAT/enhancer binding protein beta;JMJD5:Jumonji domain containing 5;AKT1S1:AKT1 substrate1;TTP:Tristetraprolin;MMP:Matrix metalloprotein.

但在一項最新的研究中,Hosios等[20]采用32P 同位素標(biāo)記PEP,結(jié)果顯示幾乎所有蛋白質(zhì)磷酸化時活性磷酸基團(tuán)均來源于ATP 而不是PEP。同時Hosios 等[20]特異性地敲除PKM2 表達(dá)后,未發(fā)現(xiàn)存在磷酸化水平明顯變化的蛋白質(zhì)。這一新的研究結(jié)果認(rèn)為PKM2不存在蛋白激酶功能。

PKM2轉(zhuǎn)錄水平的調(diào)節(jié) DNA甲基化是PKM2轉(zhuǎn)錄水平上常見的調(diào)節(jié)方式。Desai等[4]利用基因探針cg24327132研究甲基化對PKM2基因表達(dá)的影響,探針在正常組織中低甲基化而在腫瘤組織中高甲基化,并且顯示PKM2基因表達(dá)與cg24327132甲基化程度呈強(qiáng)烈的負(fù)相關(guān),暗示低甲基化有利于PKM2基因表達(dá)。

轉(zhuǎn)錄因子調(diào)節(jié)為另一種重要的調(diào)節(jié)方式。由于癌細(xì)胞內(nèi)基因突變或微環(huán)境變化使得許多轉(zhuǎn)錄因子都可以激發(fā)PKM2的高表達(dá),例如低氧誘導(dǎo)分子(hypoxia induce factor 1α,HIF-1α),核因子-κB(NF-κB),Sp1(specificity protein 1),過氧化物酶體增殖物受體γ(PPARγ)等[21]。HIF-1α在許多癌細(xì)胞中高表達(dá)并調(diào)節(jié)低氧狀態(tài)下的適應(yīng)性反應(yīng),Luo等[22-23]研究發(fā)現(xiàn)HIF-1α可以促進(jìn)PKM2基因的轉(zhuǎn)錄進(jìn)一步形成正反饋調(diào)節(jié)。HIF-1α通過與PKM基因的低氧反應(yīng)原件(hypoxia response element,HRE)結(jié)合促進(jìn)PKM基因轉(zhuǎn)錄[22,24]。也有研究發(fā)現(xiàn)PKM2過度表達(dá)導(dǎo)致信號轉(zhuǎn)導(dǎo)蛋白質(zhì)和轉(zhuǎn)錄激活物(signal transducers and activators of transcription 3,STAT3)磷酸化而進(jìn)一步激活HIF-1α轉(zhuǎn)錄[25]。轉(zhuǎn)錄因子c-Myc可以上調(diào)核抑制蛋白hnRNPA1、 hnRNPA2、 hnRNPA3,進(jìn)一步促進(jìn)PKM2表達(dá)[26-27]。除此之外,還有很多因素可以影響PKM2基因表達(dá),例如mTOR信號通路可以激活HIF-1α介導(dǎo)的PKM基因轉(zhuǎn)錄和c-Myc-hnRNPs依賴的前體mRNA剪接[28]。Sp1蛋白質(zhì)磷酸化之后可促進(jìn)PKM2的表達(dá)[29]。人第10號染色體缺失的磷酸酶及張力蛋白同源的基因(phosphatase and tensin homolog deleted on chromosome ten,PTEN)使3、4、5-三磷酸磷脂酰肌醇去磷酸化而負(fù)性調(diào)節(jié)PKM2表達(dá)[30-31]。Yang等[32]在研究癌細(xì)胞代謝過程中發(fā)現(xiàn),作為上皮細(xì)胞-間充質(zhì)細(xì)胞轉(zhuǎn)換過程重要調(diào)節(jié)因子Twist可激活β1-integrin/FAK/PI3K/AKT/mTOR信號通路并抑制P53信號通路上調(diào)PKM2表達(dá)水平。

PKM2翻譯水平的調(diào)節(jié) PKM2在翻譯水平的調(diào)節(jié)主要由miRNA所介導(dǎo),具體內(nèi)容見表2。

表 2 miRNA對PKM2的調(diào)節(jié)作用Tab 2 The effects of miRNA to PKM2

PKM2在蛋白質(zhì)水平的調(diào)節(jié) 代謝中間產(chǎn)物可在蛋白質(zhì)水平上對PKM2進(jìn)行變構(gòu)調(diào)節(jié)。PKM2存在四聚體和二聚體兩種形式,分別發(fā)揮蛋白激酶和丙酮酸激酶活性,果糖1,6-雙磷酸(FBP)和絲氨酸皆為PKM2的強(qiáng)力變構(gòu)激活劑,與PKM2結(jié)合后維持其四聚體并保持高活性狀態(tài)[40-42]。

除代謝中間產(chǎn)物對PKM2的變構(gòu)調(diào)節(jié)外,更重要的調(diào)節(jié)方式為翻譯后修飾。PKM2存在多種翻譯后修飾,對其進(jìn)行活性調(diào)節(jié),其中磷酸化最為多見,磷酸化后常導(dǎo)致PKM2與其變構(gòu)激活劑FBP解離致使活性降低[29]。常見的磷酸化位點為Tyr105,FGFR、BCR-ABL、FLT-3、HPV-16 E7等蛋白質(zhì)皆是在此位點進(jìn)行修飾[43]。除磷酸化外還存在乙?；⒘u基化等形式的翻譯后修飾,以調(diào)節(jié)PKM2活性。

表3 PKM2翻譯后修飾形式及作用Tab 3 Post-translational modification of PKM2

PHD3:Prolyl hydroxylase 3;ERK:Extracellular regulated protein kinase;PTP1B:Protein tyrosine phosphatase-1B;PCAF:P300/CBP-associated factor;HSP70:Heat shock protein 70;PIM2:Proviral integration site of murine 2;SIRT6:Sirtuins 6;MG:Methylglyoxal 0.

結(jié)語 通過對PKM2逐漸深入的研究,人們對PKM2在癌細(xì)胞中的表達(dá)、功能和調(diào)控等方面有了更深層次的理解。考慮到PKM2在腫瘤中的異常表達(dá)、在腫瘤代謝和分子調(diào)控中的顯著作用以及其功能的復(fù)雜調(diào)控,我們有理由相信PKM2將在腫瘤診斷和治療中發(fā)揮重要作用。這都使得PKM2成為腫瘤研究領(lǐng)域的焦點。

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Expression,functions and regulation of PKM2 in tumor cells

SHI Meng-kun1, YANG Xiao-dong1, SUN Feng-hao1, ZHAN Cheng△, SHI Yu1, WANG Qun1

(DepartmentofThoracicSurgery,ZhongshanHospital,FudanUniversity,Shanghai200032,China)

M2 type of pyruvate kinase (PKM2) is one of the most important regulatory molecules in glycolysis,which at high level is a major feature of tumor cells.Besides,PKM2 also regulates gene transcription and cell cycle,promoting the formation,invasion and migration of tumors.Meanwhile,PKM2 can beregulated by many transcription factors,oncogene proteins,miRNA and intermediate metabolites.Extensive studies indicated that PKM2 plays an important role in the developmental tumor.In view of the significance of PKM2 in tumor cells,it holds promise for diagnosis and treatment benefits.

M2 type of pyruvate kinase; tumor metabolism; transcrptional level

國家自然科學(xué)基金(81401875,81472225);上海市自然科學(xué)基金(14ZR1406000)

R73

B

10.3969/j.issn.1672-8467.2017.02.016

2016-05-25;編輯:王蔚)

△Corresponding author E-mail:czhan10@fudan.edu.cn

* This work was supported by the National Natural Science Foundation of China (81401875,81472225) and Natural Science Foundation of Shanghai,China (14ZR1406000).