植物多酚通過MAPK 信號通路調(diào)控腫瘤作用機制研究進展

李 瑤，廖 霞，鄭少杰，王麗穎，石 芳，左 丹，吳素蕊，明 建,3,*

（1.西南大學食品科學學院，重慶 400715；2. 中華全國供銷合作總社昆明食用菌研究所，云南 昆明 650223；3.重慶市特色食品工程技術(shù)研究中心，重慶 400715）

植物多酚通過MAPK 信號通路調(diào)控腫瘤作用機制研究進展

李 瑤1，廖 霞1，鄭少杰1，王麗穎1，石 芳1，左 丹1，吳素蕊2，明 建1,3,*

（1.西南大學食品科學學院，重慶 400715；2. 中華全國供銷合作總社昆明食用菌研究所，云南 昆明 650223；3.重慶市特色食品工程技術(shù)研究中心，重慶 400715）

腫瘤細胞的生物學過程（增殖、分化、侵襲、遷移）是癌癥發(fā)生的標志，絲裂原活化蛋白激酶（mitogenactivated protein kinase，MAPK）被證實是調(diào)節(jié)腫瘤細胞生物學過程的至關(guān)重要的信號通路。大量研究表明，天然植物多酚，如茶多酚、白藜蘆醇、花青素等對腫瘤細胞有顯著的調(diào)節(jié)作用，植物多酚介導的MAPK通路對腫瘤細胞的調(diào)節(jié)已經(jīng)引起國內(nèi)外學者的廣泛興趣。文章綜述了植物多酚通過MAPK信號通路對腫瘤細胞的調(diào)控作用，分析了不同多酚對MAPK信號通路的4 條途徑（p38、ERK-1/2、ERK5、JNK）的響應機制，旨在為明確植物多酚的抗腫瘤活性及分子機制、開發(fā)抗腫瘤保健食品或藥物提供參考。

植物多酚；絲裂原活化蛋白激酶；信號通路；抗腫瘤

癌癥是正常細胞在腫瘤發(fā)病機制中產(chǎn)生的惡性致瘤性細胞的過程[1]。該過程具有維持腫瘤細胞的增殖信號、避免生長抑制、抗細胞凋亡、使細胞永生、誘導血管生成、激活侵襲和轉(zhuǎn)移、改變能量代謝機制、防止免疫破壞等特點[2]。腫瘤細胞在增殖、凋亡、侵襲和轉(zhuǎn)移等方面的發(fā)生機制各不相同。在腫瘤細胞增殖方面，增殖信號對細胞表面受體的表達進行調(diào)控以及對信號通路元件的激活是細胞增殖和存活的關(guān)鍵，確定這些途徑的組成至關(guān)重要。在腫瘤細胞凋亡方面，腫瘤細胞是由致癌信號和過度增殖的相關(guān)DNA損傷所造成，其體內(nèi)具有相應的機制防止凋亡，如腫瘤抑制基因p53的缺失或失活、上調(diào)促生存蛋白（B-cell lymphoma-2，Bcl-2）或下調(diào)促凋亡蛋白（Bax和BIM），通過相關(guān)信號通路對腫瘤細胞凋亡進行調(diào)節(jié)[3]。在腫瘤細胞侵襲和轉(zhuǎn)移方面，是腫瘤細胞發(fā)展為侵襲身體局部組織并轉(zhuǎn)移到末梢位置的過程，激活該過程需要改變腫瘤細胞形狀，減少腫瘤細胞在其他細胞和細胞外基質(zhì)上的附著并增加其運動。而在這些腫瘤細胞在增殖、凋亡、侵襲和轉(zhuǎn)移等過程中，有絲裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）信號通路的參與介導[4]。

許多研究證實，植物多酚對腫瘤細胞的增殖、凋亡、侵襲和轉(zhuǎn)移等生物學過程有著廣泛的調(diào)節(jié)作用。本文綜述了近些年來國內(nèi)外關(guān)于植物多酚介導MAPK信號通路對腫瘤細胞的調(diào)控作用機制，總結(jié)了不同結(jié)構(gòu)植物多酚在MAPK信號通路相應途徑的特點和規(guī)律，旨在為研究植物多酚與抗腫瘤之間的關(guān)系提供參考。

圖1 MAPK信號級聯(lián)示意圖[5]Fig. 1 Schematic diagram of MAPK signaling pathways[5]

1 MAPK信號通路

MAPK信號通路，又稱有絲分裂原激活蛋白激酶信號通路[6]。它可以通過多個底物如磷酸化轉(zhuǎn)錄因子，與細胞骨架相關(guān)的細胞和酶來調(diào)節(jié)細胞各種生理過程，包括炎癥、應激、細胞生長發(fā)育、分化與死亡[7]。MAPK信號通路主要包括4 種途徑（圖1）：細胞外信號調(diào)節(jié)的激酶（extracellular regulated protein kinases-1/2，ERK-1/2）、Jun氨基末端激酶（c-Jun N-terminal kinase，JNK）、p38蛋白和細胞外信號調(diào)節(jié)的激酶5（extracellular regulated protein kinases 5，ERK5）途徑。完整的MAPK通路作用過程需要通過三級聯(lián)轉(zhuǎn)導方式依次激活。這4 種途徑需要被具體的MAP2K激活，而MAP2K可以被多種MAP3K所激活，磷酸化MAP3K激活MAP2K，MAP2K進一步磷酸化并激活MAPK。

1.1 MAPK信號通路的主要途徑

1.1.1 ERK-1/2途徑

細胞外信號調(diào)節(jié)激酶1和2（ERK-1/2）是MAPK家族的一分子。ERKs是由多種細胞外因子所激活的，其中包括生長因子、激素和神經(jīng)遞質(zhì)[8]。該細胞外因子可以通過G蛋白偶聯(lián)受體，氨酸激酶受體或通過離子通道及其他機制[9]，進而引發(fā)多種細胞內(nèi)信號響應，導致ERK級聯(lián)激活。在ERK信號通路中，ERK1或ERK2（ERK-1/2）是由MEK1/2激活，而MEK1/2又依次由Rafs（如A-Raf、B-Raf或Raf-1）激活。ERK-1/2被激活后，緊接著激活MAPKAPK激酶。蛋白激酶GSK3[10]和LKB1[11]是MAPKAPKs直接底物，如此形成了6 個層次的MAPK級聯(lián)。

ERK-1/2途徑對調(diào)控腫瘤細胞生長、分化和遷移有一定的作用。通常情況下，促進腫瘤細胞凋亡或抑制細胞增殖需要下調(diào)ERK信號通路，如β-欖香烯通過下調(diào)MAPK/ERK和PI3K/Akt/mTOR信號通路誘導腎癌786-0細胞的凋亡[12]；賴氨酰氧化酶肽通過下調(diào)MAPK/ERK信號通路抑制肝腫瘤細胞增殖并誘導其凋亡[13]。然而，并非只有抑制該通路才能促進腫瘤細胞凋亡，如α-干擾素腫瘤壞死因子相關(guān)凋亡誘導配體（TNF related apoptosis inducing ligand，TRAIL）通過下調(diào)c-casitas B細胞淋巴瘤和上調(diào)MAPK/ERK途徑誘導胃腫瘤細胞凋亡[14]。

1.1.2 JNK途徑

JNK是由“c-Jun氨基末端激酶”衍生而來。上游的MAP2K和MAP3K被絲氨酸/蘇氨酸磷酸化所激活，JNK及其同系物被蘇氨酸/酪氨酸磷酸化所激活[15-16]。

JNK調(diào)控細胞死亡、存活、增殖和分化過程主要有3 個方面的原因：一是激酶的激活或下游目標的選擇有助于消除腫瘤細胞，而腫瘤細胞死亡往往涉及到JNK的活化。二是一些腫瘤細胞增殖和轉(zhuǎn)移與JNK的活性有關(guān)[17]。三是神經(jīng)退行性疾病也與JNK介導的細胞死亡相關(guān)[18]。然而，JNK對于細胞的生長作用并非都是一致的。有研究表明，JNK能促進人類前列腺癌細胞增殖，而對乳腺癌細胞的影響卻不明顯，這可能是由于JNK底物的異質(zhì)性、酶和調(diào)節(jié)分子的結(jié)合作用影響了JNK的活性[19-20]。

1.1.3 p38途徑

p38參與了細胞增殖、細胞分化、細胞死亡、細胞遷移和侵襲等一系列復雜的生理生化過程，同時也是控制炎癥反應的一條重要通路[21]。

p38/MAPK對調(diào)節(jié)腫瘤細胞增殖、分化有非常重要的意義。一方面，p38/MAPK的激活可以誘導原發(fā)性腫瘤細胞產(chǎn)生細胞上皮-間質(zhì)轉(zhuǎn)化（epithelial-mesenchymal transition，EMT）導致腫瘤細胞的外滲，造成遷移腫瘤細胞的入侵和遷移[22]。另一方面，p38/MAPK的抑制與腫瘤細胞的抗失巢凋亡特性相關(guān)，使得循環(huán)腫瘤細胞得以存活，增加惡性腫瘤患者死亡風險[23]。p38/MAPK的高活性與ERK-1/2通路的低活性相結(jié)合，可導致腫瘤細胞休眠。研究發(fā)現(xiàn)，p38/MAPK被人乳腺上皮細胞的突變基因激活，會導致H-Ras基因特異性細胞在該細胞上進行侵襲和遷移[24-25]。

1.1.4 ERK5途徑

MAPK途徑中參與細胞調(diào)節(jié)的激酶ERK5，同其他的激酶一樣，也是由多層級聯(lián)激活的，其中WNK1充當MAP4K激酶，MAP2K主要為MEK5。ERK5能調(diào)控腫瘤細胞的增殖、凋亡、侵襲和轉(zhuǎn)移。它是第1個被證明影響HeLa細胞（宮頸癌）增殖作用的MAPK激酶[26]。同樣，在乳腺癌細胞CF7和BT474[27]、乳腺上皮細胞系MCF10A[27]、多發(fā)性骨髓瘤細胞MM1S[28]的增殖中也有類似作用。MEK5的表達增加了人胚腎細胞HEK-293與前列腺癌細胞LNCaP的增殖[29]。在晚期口腔鱗狀細胞癌中，淋巴結(jié)的轉(zhuǎn)移也與高水平的MEK5有關(guān)[30]。此外ERK5水平下降也可以減少由肝細胞生長因子（hepatocyte growth factor，HGF）誘導的乳腺癌細胞MDA-MB-231遷移[31]。

2 植物多酚通過MAPK信號通路對腫瘤細胞的調(diào)控作用

許多研究證實MAPK信號通路是調(diào)節(jié)腫瘤細胞生物學過程至關(guān)重要的途徑。而植物多酚如茶多酚、白藜蘆醇、花青素等介導MAPK信號通路對腫瘤細胞的調(diào)控已成為國內(nèi)外研究熱點。但是，不同結(jié)構(gòu)的植物多酚在調(diào)控腫瘤細胞時究竟響應哪條途徑是否有規(guī)律可循值得進一步分析和探討。

表1 植物多酚通過MAPK信號通路調(diào)控腫瘤細胞生物學途徑Table 1 MAPK signaling pathways by which plant polyphenols regulate tumor cells

2.1 白藜蘆醇

白藜蘆醇（resveratrol）是從水果中分離出來的天然多酚類化合物，對多種惡性腫瘤具有抑制效果。早就有研究指出白藜蘆醇能快速激活MEK-1、稀疏表達基因（sparse representation-based classif i er，SRC）、基質(zhì)金屬蛋白酶和表皮生長因子受體依賴性模式的MAPK。白藜蘆醇通過MAPK信號通路抑制腫瘤細胞增殖的途徑主要有兩種：一種是通過激活p38途徑抑制細胞增殖，一種是抑制ERK途徑抑制細胞增殖。

白藜蘆醇抗人結(jié)腸癌細胞的作用可通過介導上調(diào)骨形態(tài)發(fā)生蛋白（bone morphogenetic protein，BMP9）激活p38/MAPK，從而抑制人結(jié)腸癌細胞的增殖并促進其凋亡[32]。且該途徑對軟骨肉瘤細胞的增殖、遷移和凋亡有同樣作用[33]。白藜蘆醇對結(jié)腸癌細胞增殖的抑制作用也可以通過ERK-1/2通路來調(diào)節(jié)，經(jīng)過RES處理的結(jié)腸癌細胞，Bax、caspase 3和caspase 9的表達均顯著升高，而抗凋亡分子Bcl-2的表達則明顯降低；在ERK途徑中，白藜蘆醇組的RAS、Raf、MEK和ERK-1/2的表達則明顯降低，表明白藜蘆醇可通過抑制ERK-1/2途徑來抑制腫瘤細胞增殖[34]。

2.2 表沒食子兒茶素沒食子酸酯

綠茶中表沒食子兒茶素沒食子酸酯（epigallocatechin gallate，EGCG）是茶多酚中含量最豐富、生物學功能最強的活性成分[35]。由于其安全無毒副作用并且可作用于多個組織及器官的特點，EGCG作為腫瘤抑制藥物一直備受關(guān)注[36]。早期研究發(fā)現(xiàn)EGCG對丙二醇甲醚醋酸酯（2-acetoxy-1-methoxypropane，PMA）誘導的ERK和JNK激酶的激活起到一定的抑制作用，通過下調(diào)轉(zhuǎn)錄因子（activator protein-1，AP-1），從而防止胃腫瘤細胞的侵襲[37]。Yamagata等[38]研究發(fā)現(xiàn)結(jié)腸腫瘤細胞經(jīng)過EGCG處理能增加ERK-1/2、JNK1/2、p38α、p38γ和p38β的磷酸化水平。進一步研究發(fā)現(xiàn)，使用相應的激酶抑制劑處理，EGCG誘導的細胞凋亡是通過抑制ERK-1/2和Akt或者激活p38/MAPK的活性完成的。還有研究表明EGCG通過介導激活p38/MAPK，下調(diào)基質(zhì)金屬蛋白酶（metalloproteinase，MMP2）的表達抑制卵巢癌細胞的增殖和遷移[39]。

2.3 槲皮素

槲皮素（quercetin）是黃酮類化合物，具有抗腫瘤、抗炎和抗氧化等特性[40]。槲皮素可通過產(chǎn)生細胞內(nèi)活性氧（reactive oxygen species，ROS）和增加sestrin 2表達來激活p38信號通路，進而誘導結(jié)腸癌細胞的凋亡[41]。通過誘導體內(nèi)外細胞的氧化應激，槲皮素也能激活ERK途徑，誘導白血病細胞HL-60的凋亡[42]。抑制Ras/MAPK/ERK信號通路則能抑制腦膠質(zhì)瘤細胞活力和遷移，促進細胞的衰老[43]。特別是對于正常的細胞，如支氣管上皮細胞等，槲皮素介導的JNK通路對其生物學過程可表現(xiàn)出相應的反饋調(diào)節(jié)，槲皮素激活JNK并增加c-Jun和p53依賴性Bax的表達水平誘導支氣管上皮細胞的凋亡，同時JNK的失活則會抑制槲皮素減少p53和Bax的表達，進而減輕細胞的凋亡[44]。

2.4 根皮苷

根皮苷（phlorizin）是廣泛存在于蘋果、梨和各種蔬菜中的植物多酚類物質(zhì)，具有抗腫瘤活性。根皮苷可以顯著上調(diào)p53和Bax和多聚ADP核糖聚合酶的裂解，增加caspase-3活性以及活化JNK和p38途徑誘導乳腺癌細胞的凋亡[45]。研究發(fā)現(xiàn)根皮苷通過p38和JNK1/2途徑均能顯著地誘導非小細胞性肺癌細胞系A549細胞的凋亡，抑制其增殖[46]。同時，根皮苷還能抑制ERK的磷酸化，抑制12-O-十四烷酰佛波醇-13-醋酸酯（12-O-tetradecanoylphorbol 13-acetate，TPA）誘導的NF-κB活化和環(huán)氧化酶（cyclooxygenase，COX-2）表達，而促進腫瘤細胞的凋亡[47]。

2.5 花青素

花青素（anthocyanins）屬于黃酮類化合物，具有重要的抗氧化、抗炎及抗癌作用?；ㄇ嗨赝ㄟ^激活p38/MAPK途徑，下調(diào)抗凋亡蛋白（inhibitor of apoptosis protein，IAPs），促進人結(jié)腸癌HCT-116細胞凋亡[48]?；ㄇ嗨氐目鼓[瘤作用也體現(xiàn)在對JNK途徑的激活上，如黑米花色苷抑制JNK的活化，下調(diào)基質(zhì)金屬蛋白酶2（matrix metallo proteinase-2，MMP-2）和MMP-9的分泌，從而抑制乳腺癌細胞的轉(zhuǎn)移。有研究表明矢車菊素-3-O-葡萄糖苷（cyanidin-3-O-glucoside chloride，C3G）可以抑制JNK的活性[49]，防止肝細胞的凋亡，但對ER K/MA P K和p38/MAPK無抑制作用?；ㄇ嗨爻顺Ｒ姷目拱┗钚酝?，其通過MAPK途徑產(chǎn)生的抗炎活性也十分普遍，如紅樹莓花色苷能夠通過抑制MAPK（JNK通路）的活化抑制體外和體內(nèi)的炎癥反應[50]。

2.6 姜黃素

姜黃素（curcumin）是香料姜黃中最重要的功能組分，對于癌癥、動脈粥樣硬化和糖尿病等疾病具有一定的治療特性[51]。姜黃素能通過MAPK的ERK-1/2、JNK和p38/MAPK 3 種途徑對腫瘤細胞起到調(diào)控作用。研究表明小鼠暴露于煙草煙霧（tobacco smoke，TS）12 周后能激活胃和膀胱的ERK-1/2、ERK5、JNK和p38 4 種MAPK途徑，并且激活活化蛋白1（activator protein 1，AP-1），而姜黃素能有效地消除TS誘導的胃中的ERK-1/2和JNK/ MAPK途徑和膀胱中的ERK-1/2、JNK、p38 MAPK通路的活化，AP-1的活化和EMT的改變，從而對胃癌和膀胱癌起到一定的預防作用[52-53]。雖然姜黃素在體內(nèi)具有顯著的抗腫瘤活性，而藥代動力學特征則表明姜黃素的口服生物利用率差，四氫姜黃素（tetra hydro curcuminoids，THC）作為姜黃素的主要代謝產(chǎn)物，能代替p38/MAPK抑制劑有效地扭轉(zhuǎn)MCF-7細胞線粒體膜電位的耗散，并阻止THC介導的Bax表達上調(diào)、Bcl-2表達下調(diào)、caspase-3的激活及p21表達上調(diào)，表明p38/MAPK可能參與THC誘導的MCF-7細胞凋亡[54]。

2.7 其他

除上述多酚之外，還有很多植物多酚同樣能通過MAPK途徑調(diào)控腫瘤細胞的生物過程，而達到防癌抗癌的目的。齊墩果酸和大蒜素可以通過抑制MAPK/ERK信號通路抑制膠質(zhì)瘤細胞的增殖[55-56]；飛燕草色素抑制血管內(nèi)皮生長因子（vascular endothelial growth factor，VEGF）誘導的ERK-1/2和p38/MAPK磷酸化并降低轉(zhuǎn)錄因子CREB和ATF1的表達，從而抑制黑色素瘤細胞的增殖[57]。木犀草素和橄欖葉提取物通過抑制ERK-1/2活性介導的MAPK信號通路對乳腺癌細胞表現(xiàn)出抗增殖活性[58]。間苯三酚通過抑制ERK途徑磷酸化，下調(diào)下游效應激酶p70S6和翻譯起始因子RPS6和eIF4b的表達，從而促進結(jié)腸癌癌細胞的凋亡[59]。

3 結(jié) 語

本文綜述了天然植物多酚通過MAPK信號通路對腫瘤細胞生物學過程的調(diào)節(jié)作用，植物多酚抗腫瘤作用的機制表現(xiàn)為抑制腫瘤細胞增殖、遷移和侵襲，促進腫瘤細胞的凋亡。MAPK信號通路的幾條途徑的響應則表現(xiàn)為激活p38、JNK途徑和抑制ERK-1/2途徑。在這幾條途徑中，部分多酚可以響應多種激酶同時對一種腫瘤細胞發(fā)揮作用，如姜黃素可以同時激活p38、JNK、ERK-1/2途徑抑制胃癌和膀胱癌細胞的生長；根皮苷可以同時激活p38和JNK途徑誘導非小細胞性肺腫瘤細胞株A549的凋亡。當然，大部分多酚對于一種腫瘤細胞只能激活一條途徑，如花青素多通過激活JNK途徑調(diào)節(jié)細胞的生長、侵襲和遷移。

值得注意的是，本文所總結(jié)的幾類植物多酚在響應MAPK信號通路的不同途徑時涉及到ERK5的途徑較少，這可能是由于ERK5作為最晚發(fā)現(xiàn)的MAPK家族成員，還未得到科學界的廣泛重視和應用。但ERK5作為能夠調(diào)控腫瘤細胞的增殖、遷移和侵襲的MAPK激酶其作用是不能被忽視的。

隨著生物學領域?qū)χ参锒喾油ㄟ^MAPK信號通路發(fā)揮作用的研究進一步深入，MAPK信號通路的4 條途徑及其作用機制仍需要進一步闡明，不同結(jié)構(gòu)的植物多酚對這4 種途徑的選擇也需要進一步深入研究總結(jié)，為探究植物多酚發(fā)揮其抗腫瘤作用的機制提供參考依據(jù)。

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Plant Polyphenols Exert Antitumor Effect through MAPK Signaling Pathways: A Review

LI Yao1, LIAO Xia1, ZHENG Shaojie1, WANG Liying1, SHI Fang1, ZUO Dan1, WU Surui2, MING Jian1,3,*
(1. College of Food Science, Southwest University, Chongqing 400715, China; 2. Kunming Research Fungi Institute, All China Federation of Supply and Marketing Cooperatives, Kunming 650223, China; 3. Chongqing Engineering Research Center for Special Foods, Chongqing 400715, China)

The biological processes of tumor cells such as proliferation, differentiation, invasion and migration are the signs of cancer. The mitogen-activated protein kinase (MAPK) signaling pathway has been proved to be an essential pathway that can adjust the biological processes of tumor cells. A number of studies indicate that natural plant polyphenols, such as tea polyphenols, resveratrol and anthocyanins, have a signif i cant regulatory effect on tumor cells. Plant polyphenols can adjust tumor cells through the MAPK signaling pathway, which has attracted widespread research interest worldwide. This article reviews the regulating effect of plant polyphenols on tumor cells through the MAPK signaling pathway and elucidates the response mechanisms of different polyphenols to the four MAPK signaling pathways (p38, ERK-1/2, ERK5 and JNK pathways), aiming to further clarify the antitumor activity of plant polyphenols and the underlying molecular mechanisms and provide a reference for developing anticancer health foods or drugs.

plant polyphenols; mitogen-activated protein kinase; signaling pathway; antitumor

10.7506/spkx1002-6630-201707047

Q964.8；R151.2

A

1002-6630（2017）07-0296-06

李瑤, 廖霞, 鄭少杰, 等. 植物多酚通過MAPK信號通路調(diào)控腫瘤作用機制研究進展[J]. 食品科學, 2017, 38(7): 296-301. DOI:10.7506/spkx1002-6630-201707047. http://www.spkx.net.cn

LI Yao, LIAO Xia, ZHENG Shaojie, et al. Plant polyphenols exert antitumor effect through MAPK signaling pathways: a review[J]. Food Science, 2017, 38(7): 296-301. (in Chinese with English abstract)

10.7506/spkx1002-6630-201707047. http://www.spkx.net.cn

2016-06-06

國家自然科學基金面上項目（31471576）；中央高?；究蒲袠I(yè)務費專項（XDJK2016E113；XDJK2015D035）；“十二五”國家科技支撐計劃項目（2013BAD16B01）；重慶市特色食品工程技術(shù)研究中心能力提升項目（cstc2014pt-gc8001）

李瑤（1993—），女，碩士研究生，研究方向為食品化學與營養(yǎng)學。E-mail：420660685@qq.com

*通信作者：明建（1972—），男，教授，博士，研究方向為食品化學與營養(yǎng)學。E-mail：mingjian1972@163.com