第二線粒體源性胱氨酸酶激活因子及其類似物與腫瘤的相關(guān)性研究進(jìn)展

魏娟，張全安

(東南大學(xué)附屬第二醫(yī)院腫瘤科，江蘇 南京 210003)

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第二線粒體源性胱氨酸酶激活因子及其類似物與腫瘤的相關(guān)性研究進(jìn)展

魏娟，張全安

(東南大學(xué)附屬第二醫(yī)院腫瘤科，江蘇 南京 210003)

第二線粒體源性胱氨酸酶激活因子(Smac)是一種存在線粒體中并具有促凋亡作用的蛋白，Smac主要通過參與細(xì)胞凋亡的線粒體途徑和死亡受體途徑的下游反應(yīng)，特異性地與凋亡抑制因子(IAPs)結(jié)合，解除IAPs對(duì)Caspase的抑制效應(yīng)從而促進(jìn)細(xì)胞凋亡。在腫瘤細(xì)胞中，Smac的過表達(dá)可以抑制或延緩腫瘤的發(fā)生發(fā)展過程，提高細(xì)胞漿Smac含量可增強(qiáng)細(xì)胞對(duì)放化療的敏感性。人工合成的Smac類似物可通過級(jí)聯(lián)放大效應(yīng)提高腫瘤細(xì)胞對(duì)放化療的敏感性，具有高效、低毒、高通透性等優(yōu)點(diǎn)，為腫瘤的治療提供了新的方法和思路，具有重要的臨床意義。該研究就Smac、Smac類似物與腫瘤的相關(guān)性研究進(jìn)展做一綜述。

Smac；Smac類似物；細(xì)胞凋亡；腫瘤

人類第二線粒體源性胱氨酸酶激活因子(Smac),也稱為低等電點(diǎn)(PI)的凋亡蛋白抑制劑(IAP)家族直接結(jié)合蛋白(DIABLO)，是2000年Du[1]和Verhagen[2]同時(shí)發(fā)現(xiàn)的來源于線粒體的促凋亡蛋白，主要通過抑制IAPs的活性而發(fā)揮促凋亡作用。本研究就Smac的結(jié)構(gòu)、促凋亡的機(jī)制及其與Smac類似物在腫瘤發(fā)生發(fā)展、治療、預(yù)后過程中的影響作一綜述。

1 Smac的結(jié)構(gòu)

Smac主要通過參與細(xì)胞凋亡的線粒體途徑和死亡受體途徑的下游反應(yīng)，特異性地與IAPs結(jié)合，解除IAPs對(duì)半胱氨酸蛋白酶(caspase)的抑制效應(yīng)從而促進(jìn)細(xì)胞的凋亡。Smac由7個(gè)外顯子組成，位于12號(hào)染色體長(zhǎng)臂。全長(zhǎng)為1.5 kb的Smac cDNA編碼分子量約為27 kDa的239個(gè)氨基酸的前體蛋白。其末端的55個(gè)氨基酸殘基構(gòu)成了線粒體靶序列(MTS)。Smac進(jìn)入線粒體后剪切脫離線粒體靶序列，成為成熟的Smac。成熟的Smac才具有促凋亡活性。Smac蛋白在空間上有二聚體和單體兩種形態(tài)。二聚體Smac蛋白位于線粒體膜間隙內(nèi)，當(dāng)釋放入胞質(zhì)時(shí)發(fā)揮促凋亡的活性[3]，單體形態(tài)的Smac則無促凋亡功能。Smac蛋白的高表達(dá)可促進(jìn)細(xì)胞對(duì)凋亡的敏感性及對(duì)化療藥誘導(dǎo)凋亡的敏感性，而低表達(dá)則提高細(xì)胞凋亡的閾值[4]。

2 Smac的促凋亡機(jī)制

2.1 線粒體途徑 線粒體途徑也稱為內(nèi)源性途徑，當(dāng)受到如抗癌藥物、缺氧、DNA破壞、射線照射以及化學(xué)信號(hào)等的外界因素作用時(shí)，激活線粒體外膜滲透效應(yīng)使Smac從線粒體釋放到細(xì)胞質(zhì)。Smac一方面可以直接與細(xì)胞色素C(cytochrome-C )、半胱氨酸天冬氨酸蛋白酶-9前體(procaspase-9)、三磷酸脫氧腺苷(dATP)、凋亡蛋白酶活化因子-1(Apaf-1)作用，形成凋亡體激活caspase-9，進(jìn)而激活效應(yīng)因子caspase-3，caspase-6，caspase-7。另一方面通過與IAPs作用，拮抗IAPs對(duì)caspases活性的抑制作用，誘導(dǎo)細(xì)胞凋亡。Smac發(fā)揮功能的分子基礎(chǔ)是其N端的一段保守序列Ala-Val-Pro-Ile (AVPI)，通過這4個(gè)疏水氨基酸殘基同IAPs的BIR2，BIR3結(jié)構(gòu)域結(jié)合，發(fā)揮抑制IAPs的功能[6-7]。

2.2 死亡受體途徑 死亡受體途徑也稱為外源性途徑，死亡受體主要包括凋亡相關(guān)蛋白FAS、腫瘤壞死因子受體(TNFR)、腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體受體(TRAILR)等。腫瘤壞死因子(TNF)與相應(yīng)TNFR特異性結(jié)合發(fā)生寡聚化，促進(jìn)TNFR胞漿部分與接頭蛋白Fas相關(guān)死亡結(jié)構(gòu)域(FADD)和procaspase-8結(jié)合，形成DISC，激活procaspase-8自身切割后形成有活性的caspase-8，再通過TRAIL啟動(dòng)caspase-8-tBid-bax的級(jí)聯(lián)反應(yīng)，促進(jìn)成熟的Smac蛋白迅速釋放到細(xì)胞質(zhì)中，與IAPs特異性結(jié)合并解除對(duì)caspase-3的抑制作用，并使得caspase-8激活caspase-3，啟動(dòng)caspase級(jí)聯(lián)激活反應(yīng)從而導(dǎo)致靶細(xì)胞凋亡[8-9]。

2.3 Smac調(diào)控因素 Smac受調(diào)控的因素很多且過程復(fù)雜，Bcl-2家族(tBid、Bax、Bim)、Puma、JNK、caspases、cytochrome-C激發(fā)Smac從線粒體釋放到細(xì)胞質(zhì)中，而Bcl-2、Bcl-xL、Survivin、XIAP、Apollon、Erk1/2 和c-Myc 阻止其釋放過程。XIAP、c-IAP1、IAP2 和Livin促進(jìn)Smac在細(xì)胞質(zhì)中的降解和泛素化，而Survivin 和NADE 阻止Smac降解過程[10-12]。

3 Smac在腫瘤中的表達(dá)

Smac在腫瘤中廣泛表達(dá)，在不同腫瘤組織中的表達(dá)情況有差異，Yoo等[13]用免疫組織化學(xué)方法分析結(jié)果表明在胃癌、結(jié)腸癌、肺癌、卵巢癌、前列腺癌等中Smac表達(dá)率為62%，在惡性神經(jīng)鞘病、橫紋肌肉瘤、惡性皮膚纖維瘤、平滑肌肉瘤、尤文肉瘤等中Smac表達(dá)率為22%，而血管肉瘤和脂肪肉瘤中無表達(dá)。隨后，相關(guān)研究結(jié)果證實(shí)[14-16]，Smac在直腸癌、肝癌、睪丸癌等腫瘤中較正常組織呈低表達(dá)或缺失狀態(tài)，并且Smac低表達(dá)可能有抑制細(xì)胞凋亡效應(yīng)。而在宮頸癌和胃癌中恰恰相反，Smac呈高表達(dá)狀態(tài)，Shibata等[17]認(rèn)為造成表達(dá)差異的原因是由于XAF1表達(dá)量減少：XAF1是xIAP的直接抑制因子，它的降低可能增加了腫瘤細(xì)胞的凋亡閾值，從而促進(jìn)Smac的合成與釋放。而對(duì)于Smac在肺癌中的表達(dá)程度存有爭(zhēng)議。Sekimura等[18]發(fā)現(xiàn)肺癌組織中Smac mRNA的表達(dá)明顯低于正常肺組織；Hofmann等[19]證明在非小細(xì)胞肺癌(NSCLC)中Smac的低表達(dá)提高了細(xì)胞凋亡的閾值。而Zhao等[20]證明Smac mRNA在肺癌組織中的表達(dá)陽性率高于相應(yīng)的正常肺組織。Evzen等[21]亦得出Smac mRNA在NSCLC中的表達(dá)高于正常肺組織的結(jié)論，Evzen認(rèn)為其研究結(jié)果相反原因在于選擇的內(nèi)參不同。Yang等[22]發(fā)現(xiàn)Smac蛋白在NSCLC中的表達(dá)明顯高于正常組織，作者認(rèn)為該結(jié)果與Smac蛋白的促凋亡效應(yīng)并不矛盾：因?yàn)镾mac在NSCLC中高表達(dá)可增強(qiáng)促凋亡效應(yīng)，而腫瘤細(xì)胞增殖速度增快，細(xì)胞凋亡率并不減少。但導(dǎo)致同一腫瘤中表達(dá)差異的具體機(jī)制究竟是怎樣的,有何意義？現(xiàn)尚未明確，還有待進(jìn)一步深入探討。

4 Smac與腫瘤的發(fā)生發(fā)展及預(yù)后

IAPs通過抗凋亡作用參與腫瘤的發(fā)生發(fā)展過程，Smac作為IAPs的抑制劑可促進(jìn)細(xì)胞凋亡，它的高表達(dá)可以延緩或抑制腫瘤的發(fā)生發(fā)展，低表達(dá)可能預(yù)示著腫瘤侵襲力更強(qiáng)和預(yù)后更差。Yan等[23]認(rèn)為xIAP和Smac之間的平衡狀態(tài)在腫瘤發(fā)生發(fā)展過程中發(fā)揮著重要作用。在肝癌中[15]，Smac mRNA和蛋白水平較正常肝組織低，IAPs、survivin表達(dá)量的增高與肝癌進(jìn)展呈正比，說明Smac與肝癌的發(fā)生發(fā)展相關(guān)。Jia等[24]發(fā)現(xiàn)將Smac轉(zhuǎn)染至白血病細(xì)胞株中，Smac可有效地將腫瘤細(xì)胞阻滯于細(xì)胞周期的G0/G1期，說明Smac可能通過抑制細(xì)胞增殖從而延緩白血病的發(fā)生發(fā)展過程。而Espinosa等[25]發(fā)現(xiàn)宮頸癌組織有Smac mRNA的表達(dá)，正常組織中無Smac mRNA的表達(dá)，且Smac mRNA的表達(dá)與TNM分期、組織類型及病程無關(guān)。腎癌中近期兩項(xiàng)研究表明Smac mRNA和蛋白水平與腎癌的分期、分級(jí)無相關(guān)性[23-26]。但Mizutani等[27]用Western blot方法檢測(cè)腎癌組織的Smac蛋白表達(dá)，發(fā)現(xiàn)82%的腎細(xì)胞癌組織Smac表達(dá)量低于正常腎組織，且與腎癌的臨床分期及預(yù)后具有顯著的相關(guān)性。Sekimura等[18]發(fā)現(xiàn)與正常肺組織相比，肺癌組織中Smac mRNA的表達(dá)量明顯降低，T2～T4期肺癌組織的Smac mRNA表達(dá)量明顯較T1期低，Smac mRNA表達(dá)量越低的病人預(yù)后越差。Chen等[28]研究證明Smac高表達(dá)預(yù)示患者無病生存期和總生存期相對(duì)延長(zhǎng)。Zhao等[20]則證明Smac mRNA 在肺癌組織中的陽性率高于相應(yīng)的正常肺組織，Smac 蛋白在Ⅱ期NSCLC患者組織中的表達(dá)明顯高于Ⅰ期患者。且他們認(rèn)為Smac蛋白表達(dá)與Ⅰ～Ⅱ期NSCLC患者性別、年齡、血型、病理類型及生存無相關(guān)性，而與淋巴結(jié)有無轉(zhuǎn)移有關(guān)，在無淋巴結(jié)轉(zhuǎn)移者組織中明顯低于有淋巴結(jié)轉(zhuǎn)移者。

5 Smac/Smac類似物與腫瘤的治療關(guān)系

目前，腫瘤的治療強(qiáng)調(diào)的是以手術(shù)、放化療、生物治療及分子靶向治療等多種方法相結(jié)合的綜合治療。Smac作為IAPs的拮抗劑，發(fā)揮促細(xì)胞凋亡的這一活性，為Smac可以應(yīng)用于腫瘤治療提供了可靠的理論依據(jù)。提高胞漿Smac含量不僅可增強(qiáng)細(xì)胞對(duì)化療藥的敏感性，并且增強(qiáng)機(jī)體免疫系統(tǒng)對(duì)腫瘤細(xì)胞的殺傷和清除作用[29]。提高Smac含量的方法包括：一是將編碼Smac的表達(dá)載體轉(zhuǎn)染腫瘤細(xì)胞中，轉(zhuǎn)染Smac的腫瘤細(xì)胞在受到化療藥或放療作用時(shí)，促凋亡效應(yīng)較未轉(zhuǎn)染的細(xì)胞顯著增強(qiáng)。二是將由Smac蛋白衍生的含AVPI的小分子多肽與載體蛋白結(jié)合，轉(zhuǎn)染細(xì)胞，增加化療藥對(duì)腫瘤細(xì)胞的促凋亡作用。但人工切割的小分子多肽存在生物利用度差、細(xì)胞膜通透性差、生物體內(nèi)代謝穩(wěn)定性差等缺點(diǎn)。目前通過應(yīng)用熒光標(biāo)記已開發(fā)出一種高通量的藥物篩選方法，已經(jīng)成功合成比自然存在的Smac多肽促凋亡功能強(qiáng)20倍的Smac肽類的模擬物，優(yōu)點(diǎn)是高效、低毒、細(xì)胞膜通透性好等。但因需要高濃度及直接注射到腫瘤部位等缺點(diǎn)，暫無法應(yīng)用于臨床。進(jìn)而，研究人員合成了非肽類Smac類似物，通過模擬靶向蛋白-蛋白相互作用，激活腫瘤細(xì)胞的凋亡途徑，目的在于增強(qiáng)結(jié)合能力、細(xì)胞膜通透性、體內(nèi)穩(wěn)定性和生物利用度。Smac類似物可以二價(jià)結(jié)合IAP的BIR2和BIR3域，通過TNF-α環(huán)路發(fā)揮促凋亡活性。在TNF-α環(huán)路中，Smac類似物激活E3泛素酶活性，導(dǎo)致cIAPs的自身泛素化及蛋白酶體降解，從而導(dǎo)致NIK(NF-κB-inducing kinase)激活，最終導(dǎo)致NF-κB向細(xì)胞核內(nèi)轉(zhuǎn)位指導(dǎo)目的基因的表達(dá)，包括作用于TNFR1的TNFA，促使了RIP1從TNFR1釋放，去泛素化RIP1與TNFR1、caspase-8、銜接蛋白TRADD、FADD形成復(fù)合體II，從而促進(jìn)細(xì)胞凋亡。Smac類似物在腫瘤中被單獨(dú)應(yīng)用或者與化、放療聯(lián)合應(yīng)用探索抗腫瘤效應(yīng)[30-31]。相關(guān)文獻(xiàn)報(bào)告中，Huerta等[32]體內(nèi)外實(shí)驗(yàn)證明小分子Smac類似物(Smac-JP1201)可增加直腸癌細(xì)胞對(duì)放療的敏感性，并驗(yàn)證其是通過降低xIAP水平及破壞DNA修復(fù)機(jī)制誘導(dǎo)凋亡的；最近相關(guān)研究也表明Smac類似物(Smac-BV6)可通過抑制DNA修復(fù)作用而提高結(jié)直腸癌的放療敏感性[33]；Yang等[34]應(yīng)用小分子Smac類似物(SM-164)作用于頭頸部腫瘤，結(jié)果表明SM-164是通過誘導(dǎo)cIAP1降解，激活NF-κB同時(shí)促進(jìn)TNF-α產(chǎn)生，下傳凋亡信號(hào)，激活caspase導(dǎo)致細(xì)胞凋亡并增加細(xì)胞對(duì)放療的敏感性，隨后Yang等[35]研究人員又將SM-164作用于乳腺癌，結(jié)果提示SM-164可通過同樣機(jī)制提高乳腺癌細(xì)胞對(duì)放療的敏感性；Greer等[36]報(bào)告Smac 類似物JP1201 能使非小細(xì)胞肺癌細(xì)胞對(duì)多種化療藥物誘導(dǎo)的凋亡敏感性增高。最新研究表明Smac類似物可提高兒童急性淋巴細(xì)胞白血病的化療敏感性[37]。近期一項(xiàng)藥物實(shí)驗(yàn)[38]將納米顆粒與Smac多肽結(jié)合，借助納米顆粒體積小體表面積大的特點(diǎn)，在耦合Smac多肽后可以與形成多個(gè)結(jié)合面與IAPs家族結(jié)合，從而發(fā)揮更大的抗腫瘤活性。腫瘤細(xì)胞對(duì)放化療抵抗是腫瘤治療過程中的主要難題，逆轉(zhuǎn)放化療抵抗、增加放化療敏感性的靶向治療一直是腫瘤學(xué)界的研究熱點(diǎn)，Smac/Smac類似物既可促進(jìn)腫瘤細(xì)胞凋亡，同時(shí)也能發(fā)揮放化療增敏作用，由此可見，Smac及Smac類似物作為新型的靶向藥物應(yīng)用于腫瘤治療指日可待。

6 展望

近年來，Smac的促凋亡功能已得到廣泛而深入的研究和闡明，IAPs在腫瘤中的廣泛表達(dá)也為Smac提供了作用靶點(diǎn)。通過調(diào)節(jié)細(xì)胞漿Smac的含量可以有效地提高腫瘤細(xì)胞對(duì)放化療敏感性，而且通過Smac功能與結(jié)構(gòu)的研究發(fā)現(xiàn)AVPI功能序列也為開發(fā)以肽類和非肽類的Smac類似物奠定了基礎(chǔ)，將為腫瘤治療方面提供新的思路和好的應(yīng)用前景。但是應(yīng)用于臨床目前仍存在一系列問題尚待解決：如同一類腫瘤中Smac表達(dá)情況尚不統(tǒng)一,Smac的過表達(dá)對(duì)正常細(xì)胞是否有不好的影響,Smac/Smac類似物最佳治療濃度的選擇,敏感、有效的腫瘤細(xì)胞類型和化療藥物如何篩選,Smac在不同腫瘤中發(fā)揮生物學(xué)作用的具體機(jī)制,Smac類似物在人體中的毒副反應(yīng)及療效尚不明確。因此，Smac及Smac類似物在臨床的真正廣泛應(yīng)用，還需要更深入的研究，這也將為腫瘤的診斷、個(gè)體化治療開辟新的方向和途徑。

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Advances in the research of the relationship between Smac,Smac mimetic and tumor

WEI Juan,ZHANG Quanan

(DepartmentofOncology,TheSecondAffiliatedHospital,SoutheastUniversity,Nanjing,Jiangsu210003,China)

Smac is a newly found protein promoting apoptosis of mitochondria,which can promote cell apoptosis and was initially discovered independently by two groups in 2000.Smac has a pro-apoptotic effect that is mediated by its interaction with IAPs and the release of caspases from them.Overexpression of Smac in cancer cells can promote its cells apoptosis and postpone its development．Improving content of Smac in the cytoplasm can sensitize these cells to chemotherapy and radiotherapy.Smac mimetics is a potent enhancer of chemotherapy and radiotherapy,which can overcome the resistance of several cancers to anti-cancer therapies and have the advantages of high efficiency,low toxicity and high permeability.It is clear that Smas has great therapeutic potential for the treatment of cancer and has important clinical significance.In this article,we reviewed the recent advances in the study of the correlation among Smac，Smac mimetic and cancer.

Smac;Smac mimetics;Cell apoptosis;Cancer

張全安，男，主任醫(yī)師，研究方向：消化道腫瘤的診治，E-mail:13905152166@139.com

10.3969/j.issn.1009-6469.2016.10.003

2016-02-15，

2016-07-06)