劉鵬，關(guān)超

(蚌埠醫(yī)學(xué)院第二附屬醫(yī)院泌尿外科，安徽 蚌埠 233000)

IGF-IR與前列腺癌的研究進(jìn)展

劉鵬，關(guān)超

(蚌埠醫(yī)學(xué)院第二附屬醫(yī)院泌尿外科，安徽 蚌埠 233000)

前列腺癌是男性每年腫瘤相關(guān)死亡的第二大致死因。數(shù)十年來，雄激素剝奪療法是治療晚期或轉(zhuǎn)移性前列腺癌患者的黃金標(biāo)準(zhǔn)，但這種治療策略僅獲得最初的效益，最終進(jìn)展為去勢(shì)抵抗性前列腺癌，所有的治療，僅僅相對(duì)延長生存期。胰島素樣生長因子1型受體(IGF-1R)的過度表達(dá)介導(dǎo)前列腺癌細(xì)胞的生存。阻斷IGF-1R及其下游信號(hào)通路，具有抑制前列腺癌細(xì)胞增殖、分化及促凋亡的效應(yīng)。本文就IGF-1R表達(dá)與前列腺癌的發(fā)生、進(jìn)展及遷移的關(guān)系，以及靶向治療IGF-1R信號(hào)通路的研究進(jìn)展予以綜述。

IGF-1R；前列腺癌；靶向治療

前列腺癌仍然是男性的常見腫瘤，據(jù)相關(guān)文獻(xiàn)統(tǒng)計(jì)分析在2103年超過29 000例老年男性患者死于其因[1]。不管是藥物去勢(shì)或手術(shù)去勢(shì)療法，仍舊是晚期及轉(zhuǎn)移性前列腺癌的首要診療方案。然而這種治療方案只能得到近期效果，最終發(fā)展為雄激素抵抗，遠(yuǎn)期效果較差。為了進(jìn)一步理解去勢(shì)抵抗的機(jī)制，探究多個(gè)新的治療方法和改善預(yù)后，胰島素樣生長因子1型受體(Insulin-like growth factor receptor-1，IGF-1R)信號(hào)通路與前列腺癌細(xì)胞生存、進(jìn)展及遷移等分子生物學(xué)方面的研究，備受廣大學(xué)者推崇。結(jié)合目前臨床前研究，針對(duì)晚期前列腺癌患者，強(qiáng)調(diào)聯(lián)合靶向阻斷IGF-1R及其下游信號(hào)分子可能發(fā)揮最大抗腫瘤作用，本文就IGF-1R信號(hào)通路及其在前列腺癌中的作用，進(jìn)行綜述如下：

1 IGFs受體

3個(gè)配體(IGF-1，IGF-2和胰島素)、6個(gè)胰島素樣生長因子結(jié)合蛋白(IGF-binding protein，IGFBPs)和5種跨膜受體，即胰島素受體(Insulin receptor，IR)、胰島素樣生長因子1型受體、胰島素樣生長因子2型受體、胰島素受體相關(guān)受體、IGF-1R/IR雜合受體，是IGFs的基本組成元件。本文針對(duì)IGF-1R，是一個(gè)由幾個(gè)二硫鍵連接兩個(gè)α異源胞外鏈和兩個(gè)跨膜β鏈的跨膜酪氨酸激酶受體。配體結(jié)合后α鏈，內(nèi)在的酪氨酸激酶活性的β鏈被激活，導(dǎo)致近膜區(qū)和C-末端結(jié)構(gòu)域的酪氨酸激酶磷酸化，為胰島素受體底物(IRS)-1和Src同源結(jié)構(gòu)域轉(zhuǎn)化蛋白(SHC)提供對(duì)接的基板。IRS-1磷酸化后激活磷脂酰肌醇3激酶(PI3K)/Akt通路，磷酸化的Src同源結(jié)構(gòu)域有轉(zhuǎn)化蛋白(SHC)和IRS-1可以招募生長因子受體結(jié)合蛋白2(Grb2)，聯(lián)合鳥嘌呤核苷酸交換因子(Son of sevenless，SOS)和激活Ras和Raf-1/絲裂原激活蛋白激酶激酶(MEK)/細(xì)胞外信號(hào)調(diào)節(jié)激酶(ERK)信號(hào)通路[2]。Clusterin(CLU)是細(xì)胞凋亡抑制蛋白，即叢生蛋白，高表達(dá)在去勢(shì)抵抗性前列腺癌(CRPC)。據(jù)相關(guān)研究報(bào)道，IGF-1R通過順序激活STAT3和TWIST1誘導(dǎo)CLU表達(dá)，認(rèn)為這一信號(hào)通路在前列腺癌發(fā)病機(jī)制中起著重要作用[3]。顯然，IGF-1R的超表達(dá)，誘導(dǎo)CLU過度表達(dá)，發(fā)揮抗凋亡效應(yīng)。

據(jù)報(bào)道，IR和IGF-1R在多種癌癥，包括前列腺癌、乳腺癌、骨肉瘤及甲狀腺癌中是過度表達(dá)的[4-5]，從而提出假設(shè)，它們可能形成混合型受體。IGF-1R與IR是高度同源的，氨基酸激酶結(jié)構(gòu)域同源性高達(dá)84%和100%的保守性在ATP結(jié)合域[6]。因此，IGF-1R/胰島素混合受體包括IR和IGF-1R各自的一個(gè)α亞基和一個(gè)β亞基，并由二硫鍵鏈接而成[7]。胰島素結(jié)合具有高親和力IR-a、IR-b及IGF-1R；IGF-1結(jié)合具有高親和力的IGF-1R和混合受體IGF-1R/IR-a或IGF-1R/IR-b；IGF-2結(jié)合IR-a、IGF-1R或混合受體IGF-1R/IR-a[8]。在人類癌癥的發(fā)生發(fā)展機(jī)制探究中，強(qiáng)調(diào)IR/IGF-1R混合受體結(jié)合胰島素和胰島素樣生長因子-1(IGF-1)發(fā)生自身磷酸化，具有誘導(dǎo)癌細(xì)胞增殖的作用，這表明IR/ IGF-1R混合受體是IGFs信號(hào)通路中主要的調(diào)節(jié)點(diǎn)[9-10]。

2 IGF-1R信號(hào)通路

IGF-1R激活是依賴于配體的。IGF-1/2結(jié)合IGF-1R調(diào)節(jié)細(xì)胞生理功能，通過兩種下游信號(hào)通路。IGF-1R活化后橫跨膜的β亞基結(jié)構(gòu)重排，導(dǎo)致胞質(zhì)內(nèi)酪氨酸激酶結(jié)構(gòu)域反向自磷酸化(一個(gè)激酶結(jié)構(gòu)域磷酸化另一個(gè))并減弱該激酶結(jié)構(gòu)域的自抑制作用。磷酸化激活的IGF-1R募集和激活下游信號(hào)蛋白質(zhì)包括IRS-1、IRS-2和SHC。IGF-1R介導(dǎo)第一個(gè)下游信號(hào)通路，即PI3K/AKT信號(hào)通路，首先被磷酸化激活的是胰島素受體底物(IRS)1-4和Src同源性/膠原蛋白質(zhì)(SHC)，磷酸化的IRS激活(PI3K)/AKT信號(hào)通路中的3、4、5-三磷酸磷脂酰肌醇(PIP3)，最后激活A(yù)KT。AKT即蛋白激酶B，具有誘導(dǎo)抗凋亡蛋白生成的功能。因此IGF-1R介導(dǎo)的(PI3K)/AKT信號(hào)通路具有促細(xì)胞有絲分裂、細(xì)胞增殖、細(xì)胞周期控制和抑制細(xì)胞凋亡的生物學(xué)效應(yīng)[11]。IGF-1R介導(dǎo)的第二個(gè)信號(hào)通路，即MAPK/ERK信號(hào)通路，最初是聚集鳥嘌呤核苷酸交換因子(SOS)通過支架蛋白Grb2結(jié)合于IRS-1或SHC。SOS形成蛋白復(fù)合物，使RAS和RAF蛋白聚集于細(xì)胞內(nèi)表面。順序活化Ras蛋白介導(dǎo)細(xì)胞內(nèi)信號(hào)級(jí)聯(lián)反應(yīng)，激活Raf蛋白從而激活絲裂原活化蛋白激酶(MAPK/ERK)信號(hào)通路，最后激活ELK-1等底物誘導(dǎo)細(xì)胞的增殖與分化[12]。

在某些細(xì)胞內(nèi)，IGF-1R還可以磷酸化激活兩面神激酶(Janus kinase，JAK)，磷酸化的JAK蛋白順序激活STAT蛋白質(zhì)。正如JAK1和JAK2的過度表達(dá)阻滯了細(xì)胞因子信號(hào)傳導(dǎo)抑制因子(Suppressor of cytokine signaling，SOCS)的表達(dá)，從而增加STAT3的磷酸化水平。據(jù)報(bào)道在體外和體內(nèi)IGF-1/IGF-1R都參與STAT3的活化[13]和STAT-3被認(rèn)為是IGF-1R信號(hào)通路中又一關(guān)鍵信號(hào)蛋白。STAT3可能是其下游的靶向信號(hào)分子，誘導(dǎo)致癌基因的超表達(dá)，參與腫瘤的發(fā)生及進(jìn)展。

3 IGF-1R與前列腺癌的進(jìn)展

絕大多數(shù)的復(fù)發(fā)性前列腺癌患者對(duì)標(biāo)準(zhǔn)的雄激素阻斷療法是敏感的，然而，這種疾病最終進(jìn)展為去勢(shì)抵抗型前列腺癌。據(jù)報(bào)道有關(guān)這種進(jìn)展的多個(gè)機(jī)制如下[14-15]，其中包括：(1)雄激素受體的表觀遺傳突變可激活雄激素非依賴性受體；(2)選擇性剪接雄激素受體，組成性激活雄激素受體，通過刪除配體結(jié)合結(jié)構(gòu)域；(3)生長因子和細(xì)胞因子介導(dǎo)反式激活雄激素受體；(4)在前列腺腫瘤微環(huán)境中通過胞內(nèi)分泌類固醇激素合成途徑維持瘤內(nèi)雄激素水平[16]。在雄激素去勢(shì)術(shù)后，疾病進(jìn)展為雄激素非依賴型的機(jī)制，是IGF-1R介導(dǎo)的反式激活雄激素受體，通過激活PI3K/AKT信號(hào)通路。這一信號(hào)通路的激活可表明有多個(gè)機(jī)制介導(dǎo)去勢(shì)抵抗前列腺癌的進(jìn)程[17-19]，其途徑包括雄激素受體的直接磷酸化、WNT/GSK3通路的激活、NF-κB通路的激活及叉形頭(Forkhead box-O，F(xiàn)OXO)轉(zhuǎn)錄因子家族的激活。這些研究表明，對(duì)于前列腺癌患者采用靶向阻斷IGF-1R信號(hào)通路聯(lián)合雄激素剝奪療法可能獲得協(xié)同治療效果。

4 IGF-1R與前列腺癌的轉(zhuǎn)移

IGF-1R信號(hào)通路介導(dǎo)前列腺癌轉(zhuǎn)移的機(jī)制是錯(cuò)綜復(fù)雜的及仍需要大量實(shí)驗(yàn)數(shù)據(jù)驗(yàn)證的。此外，前列腺癌細(xì)胞實(shí)現(xiàn)轉(zhuǎn)移的潛能是通過IGF-1R信號(hào)修改細(xì)胞的粘附力和遷移性，然而這也有賴于腫瘤細(xì)胞強(qiáng)大的增殖能力[20]。IGF-1R誘導(dǎo)血管內(nèi)皮生長因子(Vascular endothelial growth factor，VEGF)C過度表達(dá)促血管生成和淋巴管生成，在多數(shù)惡性腫瘤伴淋巴轉(zhuǎn)移中這一跡象是普遍存在的[21]。VEGF-C在前列腺癌伴淋巴結(jié)轉(zhuǎn)移的晚期患者中呈過度表達(dá)的跡象。進(jìn)一步研究表明，全雄激素阻斷后可以上調(diào)VEGF-C的表達(dá)可能是通過下調(diào)IGF-1R的表達(dá)和激活叉頭轉(zhuǎn)錄因子FOXO-1[19]。

在骨轉(zhuǎn)移的情況下，骨源性IGF-1通過活化IGF-1R/Akt/NF-κB信號(hào)通路來連接骨細(xì)胞與轉(zhuǎn)移癌細(xì)胞之間的交聯(lián)[22]。因此，IGF-1R和NF-κB信號(hào)通路的抑制可能是一種很有前途的腫瘤骨轉(zhuǎn)移的干預(yù)治療，而聯(lián)合靶向治療IGF-1R和VEGF可能更有效的治療淋巴轉(zhuǎn)移。

此外，在炎癥相關(guān)前列腺癌的轉(zhuǎn)移中，IGF-1R信號(hào)通路同樣具有不可忽視的作用。據(jù)Rojas等[23]報(bào)道anti-IL-6單克隆抗體CNTO328應(yīng)用于晚期前列腺癌并沒有獲得滿意的療效，提出白細(xì)胞介素6(Interleukin-6，IL-6)可能通過STAT3和IGF-1R信號(hào)通路促進(jìn)前列腺腫瘤的發(fā)生及侵襲性進(jìn)展。對(duì)晚期前列腺癌患者的治療，取代抗IL-6抗體阻斷IL-6信號(hào)，而靶向抑制IGF-1R聯(lián)合STAT3可能是一種更好的治療策略，或許更是預(yù)防炎癥相關(guān)前列腺癌的新穎手段。

5 IGF-1R酪氨酸激酶抑制劑、IGF-1R單克隆抗體與臨床應(yīng)用

相關(guān)文獻(xiàn)報(bào)道，BMS-754807通過競(jìng)爭(zhēng)性結(jié)合IGF-1R受體酪氨酸激酶的ATP，是一種口服的小分子抑制劑。隨著BMS-754807聯(lián)合多西他賽治療除了可以降低腫瘤細(xì)胞增殖率和提高凋亡率，同時(shí)也能縮小腫瘤體積[24]?；罨疎GFR和IGF-1R，再加上這兩個(gè)信號(hào)通路之間交叉對(duì)話，可能介導(dǎo)降低前列腺癌細(xì)胞對(duì)放射治療的敏感性。據(jù)報(bào)道，用人類雄激素非依賴性前列腺癌細(xì)胞(DU145、PC3、ARCaPE、ARCaPM)作為實(shí)驗(yàn)對(duì)象，然后以厄洛替尼(10 μm)和AG1024(10 μm)處理這四種癌細(xì)胞1 h，然后用2 Gy射線照射[25]。數(shù)據(jù)表明，由射線照射加抑制EGFR和IGF-1R的腫瘤細(xì)胞，相比單獨(dú)照射處理或照射加阻止單一受體，四種前列腺癌細(xì)胞存活率顯著降低，凋亡率明顯增加；靶向抑制EGFR和IGF-1R為前列腺癌放療敏感性低下的患者提供了新的治療途徑。OSI-906是一個(gè)競(jìng)爭(zhēng)性結(jié)合IGF-1R信號(hào)軸ATP的小分子抑制劑。具有抗腫瘤活性的OSI-906已在乳腺癌[26]、卵巢癌[27]和肺癌[28]等實(shí)驗(yàn)?zāi)Ｐ椭斜蛔C實(shí)。目前，相關(guān)報(bào)道研究苦鬼臼毒素(PPP)作為一種單一口服給藥的方式或聯(lián)合其他藥物在晚期實(shí)體腫瘤患者，PPP通過阻滯IGF-1R受體自身磷酸化水平，發(fā)揮抗增殖和促凋亡[29]。NVP-AEW541是吡咯[2，3-d]嘧啶衍生的酪氨酸激酶抑制劑對(duì)IGF-1R受體具有高選擇性。胰島素樣生長因子通過抑制DC細(xì)胞的成熟，來介導(dǎo)腫瘤細(xì)胞免疫逃逸，NVP-AEW541阻斷IGFs與IGF-1R結(jié)合的作用，恢復(fù)DC細(xì)胞的成熟及抗腫瘤功能，可能是腫瘤免疫治療的新突破口[30]。

人類單克隆抗體的靶向結(jié)合IGF-1R胞外結(jié)構(gòu)域，阻斷IGF-1R介導(dǎo)的下游信號(hào)通路。相應(yīng)的藥物抗體已應(yīng)用到臨床前和臨床階段。這些抗體主要有EM164、IMC-A12、CP-751871及MK-0646等。EM164主要應(yīng)用于臨床上晚期轉(zhuǎn)移性腫瘤患者，其療效需要大量臨床資料來證實(shí)[31]。在多種癌細(xì)胞株，IMC-A12阻止配體與IGF-1R受體結(jié)合，來抑制IGF-1R下游MAPK和PI3K信號(hào)通路，達(dá)到一定程度抗腫瘤的效果，1期和2期臨床試驗(yàn)已顯示IMC-A12是安全的和高效益的治療性抗體[32]。其他藥物及miRNA針對(duì)IGF-1R的相關(guān)性研究如下：二烯丙基二硫是大蒜的主要成分之一，Arunkumar等[33]報(bào)道，二烯丙基二硫可以降低雄激素非依賴性前列腺癌細(xì)胞(PC-3)的存活率，誘導(dǎo)癌細(xì)胞的凋亡，通過調(diào)節(jié)IGF-1R的表達(dá)，抑制AKT磷酸化的水平。它可能是雄激素非依賴性前列腺癌治療的又一手段。Kato等[34]探究，二甲雙胍對(duì)雄激素非依賴性前列腺癌細(xì)胞(PC-3)處理48 h后，測(cè)定IGF-1R的mRNA表達(dá)量顯著下降，IGF-1R蛋白的表達(dá)量也明顯減少。此外，由于二甲雙胍的干預(yù)治療，減弱了IGF-1R激活ERK1/2及AKT信號(hào)通路的作用。結(jié)果表明，二甲雙胍是一種強(qiáng)效的胰島素樣生長因子/受體系統(tǒng)的抑制劑，可能有利于前列腺癌的治療。印苦棘內(nèi)酯是楝樹的一個(gè)重要組成部分，Raja Singh等[35]報(bào)道，用印苦棘內(nèi)酯處理的雄激素非依賴性前列腺癌細(xì)胞(PC-3)株，蛋白質(zhì)印跡法測(cè)定PI3K、Akt、IGF-1及IGF-1R的表達(dá)降低，凋亡蛋白(Caspases 8、3、10、9)的表達(dá)增加。結(jié)果表明，印苦棘內(nèi)酯可能通過IGF-1R/PI3K/Akt信號(hào)途徑介導(dǎo)細(xì)胞凋亡和抗增殖，是一種有效的生物抗癌劑。減少miRNA let-7a的表達(dá)和激活I(lǐng)GF-1R信號(hào)通路都參與前列腺癌的發(fā)生與進(jìn)展。Wang等相關(guān)研究報(bào)道，用Let-7a1干預(yù)人前列腺癌PC-3細(xì)胞，結(jié)果發(fā)現(xiàn)Let-7a1直接結(jié)合于IGF-1R mRNA 3'非編碼區(qū)的T1與T2位點(diǎn)，抑制IGF-1R的表達(dá)。Let-7a1介導(dǎo)下調(diào)IGF-1R的表達(dá)，相應(yīng)的抑制其下游信號(hào)分子Elk1的激活與c-fos的表達(dá)，起著抗增殖、促凋亡及干擾細(xì)胞周期的效應(yīng)。針對(duì)前列腺癌的診療，特別是前列腺癌進(jìn)展為激素難治性，Let-7a有望是一種新穎的基因治療策略[36]。

6 展 望

隨著對(duì)IGF-1R信號(hào)通路的深入透徹的探索，其下游的信號(hào)通路及靶基因，與前列腺癌及多種腫瘤的生長、進(jìn)展及遷移緊緊相連。大量相關(guān)的研究報(bào)道，IGF-1R的過度表達(dá)可能是前列腺癌的復(fù)發(fā)及最終進(jìn)展為去勢(shì)抵抗性前列腺癌的關(guān)鍵因素之一。然而，針對(duì)IGF-1R的靶向藥物治療，已獲得相應(yīng)的臨床療效，相對(duì)延長晚期前列腺癌患者的生存時(shí)間，但伴隨的藥物副作用不可忽視。進(jìn)一步的探究IGF-1R及其他信號(hào)通路與前列腺癌的發(fā)生、發(fā)展及惡化轉(zhuǎn)移的多個(gè)機(jī)制，研制出多種特異性高效性靶向藥物，采用聯(lián)合用藥的方案，降低藥物不良反應(yīng)，絕對(duì)延長生存期，這將給晚期前列腺癌及其他晚期腫瘤患者帶來福音。

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Progress in the study of insulin-like growth factor receptor-1 and prostate cancer.

LIU Peng,GUAN Chao. Department of Urology Surgery,the Second Affiliated Hospital of Bengbu Medical College,Bengbu 233000,Anhui,CHINA

Prostate cancer is the second leading cause of cancer related deaths in men each year.For decades, androgen deprivation therapy is and has been the gold standard for treatment of patients with advanced or metastatic prostate cancer,but this treatment strategy only shows benefit initially and the tumors recur as castration-resistant prostate cancer eventually,with only relatively prolonged survival.Overexpression of the insulin-like growth factor-1 receptor(IGF-1R)has been shown to mediate the survival of prostate cancer cells.Blocking IGF-1R and its downstream signaling pathway can inhibit the proliferation,differentiation and apoptosis of prostate cancer cells.Here is to make a review of the relationship between IGF-1R expression and the occurrence,progression and migration of prostate cancer, with research progress of targeting IGF-1R signaling pathway.

Insulin-like growth factor-1 receptor(IGF-1R);Prostate cancer;Targeted therapy

R737.25

A

1003—6350（2016）10—1650—04

10.3969/j.issn.1003-6350.2016.10.034

2015-07-23)

關(guān)超。E-mail：Gc666516@yahoo.com.cn