修回日期: 2012-01-03
接受日期: 2012-02-06
在线出版日期: 2012-02-08
激活的腺苷酸活化蛋白激酶(adenosine monophosphate activated protein kinase, AMPK)可通过调节胆固醇代谢、脂肪酸合成及蛋白质合成, 影响消化系肿瘤细胞的生长和增殖; 通过调节细胞周期进而促进消化系肿瘤细胞周期停滞. 活化的AMPK可激活caspase-9进而诱导消化系肿瘤细胞凋亡; AMPK还与消化系肿瘤的新生血管形成及侵袭转移等密切相关. 本文拟对AMPK与消化系肿瘤的关系及其分子机制作一综述.
引文著录: 程卫杰, 程继东, 荆绪斌. AMPK与消化系肿瘤的研究进展. 世界华人消化杂志 2012; 20(4): 304-309
Revised: January 3, 2012
Accepted: February 6, 2012
Published online: February 8, 2012
Activation of adenosine monophosphate activated protein kinase (AMPK) not only affects gastrointestinal cancer cell growth and proliferation by regulating cholesterol metabolism, fatty acid synthesis and protein synthesis, but also promotes gastrointestinal cancer cell cycle arrest by regulating cell cycle progression. Moreover, activation of AMPK activates caspase-9 and then induces the apoptosis of gastrointestinal cancer cells. In addition, AMPK is closely related with angiogenesis, invasion and metastasis of gastrointestinal cancer. This review aims to elucidate the relationship between AMPK and gastrointestinal cancer.
- Citation: Cheng WJ, Cheng JD, Jing XB. AMPK and gastrointestinal carcinoma. Shijie Huaren Xiaohua Zazhi 2012; 20(4): 304-309
- URL: https://www.wjgnet.com/1009-3079/full/v20/i4/304.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i4.304
消化系肿瘤是人类健康的3大杀手之一, 严重危害着人类的健康, 有关肿瘤的发病机制、治疗手段、治疗靶点已成为科学研究的重点和热点之一. 腺苷酸活化蛋白激酶(adenosine monophosphate activated protein kinase, AMPK)是一种能被AMP激活的蛋白激酶, 是真核细胞内一类与细胞能量代谢有关激酶家族中的一员, 被称为"能量感受器". AMPK作为能量感受器, 在缺氧、缺血、葡萄糖丢失及运动时被激活[1]. 研究发现, 激活的AMPK与肿瘤的生长增殖、细胞周期、凋亡、新生血管形成及侵袭转移密切相关[2-4]. 因此, 探讨AMPK与肿瘤的关系具有重要的意义. 流行病学资料显示, AMPK的激活剂二甲双胍能降低消化系肿瘤的发病率和死亡率[5]. AMPK与消化系肿瘤的研究也越来越多. 本文拟对AMPK与消化系肿瘤的关系及其分子机制作综述如下.
AMPK是由催化亚基α、调节亚基β和γ构成的异源三聚体. α亚基含有1个N端激酶结构域和1个C端结构域, N端是催化核心部位, 有典型的丝氨酸/苏氨酸激酶结构域, C端则主要负责活性的调节以及联系β和γ亚单位, 并参与AMP的结合; β亚基N端的十四烷酰化序列对蛋白质具有固定的作用, 对AMPK活性的调控也有重要作用, 为形成稳定有活性的复合物所必需[6]; γ亚基主要作用是参与细胞质的导向、蛋白与蛋白的相互作用和蛋白质活性的调节. AMPK亚单位在不同组织器官的分布不同, 且各个亚基均有多个同工型, 因此形成的三聚体亦各异, 可能与组织特异性靶分子的调节有关[7].
体内许多因素如缺血、缺氧、葡萄糖缺乏、饥饿等均可导致AMP/ATP比值显著增高, 使AMPK系统激活. 目前, 已阐明AMP可以通过3种方式共同协调激活AMPK: (1)与AMPK-γ亚基上Bateman结构域结合, 异构激活AMPK; (2)激活上游激酶, 从而磷酸化AMPK-α亚基的Thr172位点[8,9]; (3)抑制蛋白磷酸酶对AMPK-α亚基Thr172位点的去磷酸化作用[10,11]. 这种协调激活模式意味着能量的微小变化, 即胞浆中AMP/ATP比例的轻微升高, 就会激活AMPK, 引起一系列的级联反应, 放大信号, 使机体迅速作出反应.
到目前为止, 能激活AMPK的上游激酶主要有: (1)LKB1, 又称丝氨酸/苏氨酸蛋白激酶11(serine/threonine protein kinase 11, STK11), 是由LKB1基因编码的丝氨酸/苏氨酸蛋白激酶家族的成员, 是一种抑癌基因, 他可以直接磷酸化AMPK-α亚单位上的172位苏氨酸而激活AMPK[12,13]; (2)钙调蛋白依赖性蛋白激酶激酶-β(calmodulin-dependent protein kinase kinase-β, CaMKK-β), 他主要通过增加细胞内Ca2+水平从而激活AMPK[14]. 其他酶包括转化生长因子-β激活酶-1(TGF-beta activated kinase-1, TAK-1)和共济失调毛细血管扩张突变(ataxia-telangiectasia mutated, ATM)激酶[15,16].
5-氨基-4-甲酰胺咪唑核糖核苷酸(5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside, AICAR)是较早发现并广泛使用的一种AMPK激动剂, 作为一种腺苷类似物, 他可通过腺苷转运体被细胞摄取, 并被腺苷激酶磷酸化形成AMP的类似物ZMP, 从而激活AMPK信号传导通路[17]. 最新研究表明, 2个临床应用于降糖治疗的药物: 二甲双胍和噻唑烷二酮类药物, 已被认为能激活AMPK[18]. 二甲双胍通过抑制呼吸链复合体I的活性, 抑制ATP的合成从而间接激活AMPK. 另外, AMPK同样能被激素类和细胞活素类所激活, 包括瘦蛋白和脂联素、白介素-6和纤毛神经因子等[18].
体外研究发现, AMPK可通过调节代谢所需的酶类从而调节肿瘤的生长和增殖. 研究表明, 众多肿瘤的发生与机体能量代谢异常有关. 很多代谢相关激酶的活性异常增高与肿瘤的发生发展密切相关, 并受AMPK调控. AMPK通过其本身生物学效应下调各种合成反应的相关酶类, 抑制肿瘤细胞脂类和蛋白质等生物大分子的合成, 从而遏制肿瘤增殖. 已有实验证明在肝癌细胞中, 运用AMPK的激活物表没食子儿茶素没食子酸酯(epigallocatechin gallate, EGCG)可以下调脂肪酸合成酶(fatty acid synthase, FASN)和雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)的表达而抑制肿瘤细胞的增殖[19]. AMPK可通过以下途径影响消化系肿瘤.
近年来, 他汀类药物被报告具有抗肿瘤增殖的作用. 他汀类是最常用的降低胆固醇的药物, 他通过抑制羟甲基戊二酸单酰辅酶A(hydroxymethylglutaryl coenzyme A, HMG-COA)还原酶而发挥作用. HMG-COA还原酶是AMPK的反应底物, AMPK活化可以抑制HMG-COA还原酶的活性, 从而导致胆固醇合成减少[20,21]. 因此, 活化的AMPK可能通过抑制HMG-COA还原酶的活性, 进而导致胆固醇合成减少, 使消化系肿瘤的生长、增殖受抑制.
乙酰辅酶A羧化酶(Acetyl CoA carboxylase, ACC)和FASN是脂肪酸合成的限速酶, 在肿瘤的形成中起到关键作用. 许多肿瘤细胞脂肪酸合成明显增加, 而非肿瘤细胞(除脂肪细胞外)的脂肪酸合成作用非常低下. 肿瘤细胞的快速增殖, 需要脂肪酸的大量生成. 研究发现, 二甲双胍可通过激活AMPK进而阻止高能量为结肠癌细胞带来的快速生长, 主要是通过降低胰岛素水平、抑制FASN的表达, 并可通过抑制ACC的磷酸化影响脂肪酸合成[22]. 在肝癌细胞中, 活化的AMPK能抑制脂肪合成并增强脂肪酸氧化[23,24]. 还有研究发现, 在结肠癌细胞中, 胰岛素样生长因子(Insulin-like growth factor-1, IGF-1)可双重调控ACC的活性从而影响细胞的脂肪代谢[25]. 因此, 活化的AMPK可能通过抑制脂肪酸合成从而抑制消化系肿瘤的生长、增殖.
雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)是肿瘤发生中一个高活性表达的蛋白激酶, 是细胞生长、分化、生存的一个调控中心, 也与细胞凋亡有密切关系. 研究证实mTOR是AMPK主要的下游靶点之一[26]. PI3K/Akt/mTOR信号途径是真核生物调控细胞生长的一条重要的信号途径. 在血小板衍生生长因子(platelet-derived growth factor, PDGF)、表皮生长因子(epidermal growth factor, EGF)等生长因子的刺激下, PI3K-Akt通路被激活, 从而激活mTOR[27]. 随后mTOR磷酸化2个下游分子核糖体S6蛋白激酶(ribosomal s6 kinase, S6K)和真核生物翻译起始因子4E结合蛋白1, 从而上调蛋白质合成, 促进细胞生长和增殖. 研究发现, 活化的AMPK可通过Akt依赖途径抑制mTOR, 进而抑制结肠癌细胞蛋白质合成[28]. 另外, 活化的AMPK可以磷酸化结节性硬化复合体2(Tuberous sclerosis complex 2, TSC2)上的另外2个氨基酸残基Thr1227和Ser1345, 从而激活TSC, 促使TSC1/TSC2复合物的形成, 抑制了mTOR的活性, 从而抑制蛋白质的合成[29]. 因此, AMPK通过一系列途径下调mTOR信号, 直接或间接地抑制蛋白质合成, 继而控制肿瘤细胞生长. 另外, AMPK已经被证明通过磷酸化或调节几个其他分子从而调节细胞代谢、生长、生存和自噬, 例如: P300组蛋白乙酰转移酶和叉头框蛋白03(forkhead box O3, FOXO3)[30-32].
AMPK主要在细胞周期的启动机制和监控机制上调节消化系肿瘤的生长和增殖.
细胞周期能否启动进行细胞增殖, 主要调控点在G1期, 他决定细胞是否通过G1期进入S期, 这一调控点被称为"起始点". 而这一控制点主要是在细胞周期蛋白(cyclin), 周期蛋白依赖性蛋白激酶(cyclin dependent kinase, CDK)和周期蛋白依赖性蛋白激酶的抑制性蛋白(CDKI)共同调控完成的. cyclin也称周期素, 指合成和降解与细胞周期相关, 并能与相应的CDK形成复合物的一类蛋白. 他们与CDK形成复合物以决定激酶特异性和酶活性. CDK是指与周期蛋白结合才具有酶活性的激酶类. CDKI是一类细胞周期蛋白依赖激酶抑制剂、主要对细胞周期起负性调控作用, 大部分都是抑癌基因的编码产物, 以多肽的分子量大小来命名. 主要有2大家族, INK4(Inhibitor of CDK4)和CIP/KIP(Kinase inhibition protein). 细胞周期启动机制主要有2条途径, 一是cyclinD/CDK4; 二是cyclinE/CDK2. 研究发现, 在葡萄糖缺乏的情况下, 激活的AMPK诱导P53磷酸化从而启动细胞周期的停滞[33], 其可能的机制是活化的AMPK可诱导P53磷酸化并启动P21合成, P21是一种CDKI, 其可与多种Cyclin-CDK结合, 形成三聚体, 导致复合物cyclin D-CDK4和CyclinE-CDK2活性受抑制, 抑制Rb蛋白磷酸化, 非磷酸化Rb蛋白与E2F紧密结合, 使之失活, 从而阻止细胞从G1期进入S期. 有研究发现, P53诱导肝癌细胞凋亡可能的途径是通过激活AMPK[34].
细胞周期的运行, 是在一系列称为检查点的严格检控下进行的. 细胞周期检查点(cell cycle check point)是指控制细胞增殖周期中的限速位点, 是细胞周期中的一套保证DNA复制和染色体分配质量的检查机制. 细胞周期检查点主要在4个时相点发挥作用: (1)G1/S期检查点; (2)S期检查点; (3)G2/M期检查点; (4)中/后期检查点. 转化生长因子-β(transforming growth factor-β, TGF-β)可下调cyclinD和CDK4的表达以及促进P21、P27和P15等产生, 使细胞周期阻滞在G1期. 有研究表明, AICAR可通过激活AMPK, 从而激活TGF-β, 使结肠癌细胞周期停滞于G1期[35]. 有研究发现脂联素通过激活AMPK进而使结肠癌细胞周期停滞于G1期, 其可能机制是AMPK激活导致cyclin D1 mRNA及蛋白表达下降, 诱导P21和P27表达, 抑制cyclin E/CDK2复合体活性, 从而阻止细胞从G1期进入S期的进程, 导致结肠癌细胞周期停滞的发生[36].
肿瘤的发生不仅是肿瘤细胞无限增殖的结果, 也与肿瘤细胞的凋亡受阻有关. 凋亡的过程主要分为细胞凋亡的启动和凋亡的执行. 细胞凋亡的启动是细胞在接受信号刺激后胞内一系列程序的起动, 主要途径包括细胞凋亡的膜受体通路和细胞色素C释放和半胱天冬蛋白酶(caspases)激活的生物化学途径. 凋亡过程的详细机制尚不完全清楚, 但已经确定caspases在凋亡执行中起着必不可少的作用. 有研究表明, 槲皮素通过激活AMPK和P53依赖途径诱导结肠癌细胞凋亡[37], 其可能的机制为: 活化的AMPK通过P53途径使凋亡体活化, 接着活化caspase-9前体, 进而激活执行caspase即caspase-3活化, 切割底物, 激活核纤层蛋白、肌动蛋白等蛋白酶及核酸内切酶, 抑制DNA修复酶, 破坏细胞骨架蛋白和核蛋白, 导致细胞凋亡. 另有研究发现二甲双胍能诱导P53缺失的HCT116结肠癌细胞凋亡, 并选择性抑制这些细胞接种后的生长, 而在含野生型P53的HCT116细胞中不能抑制其生长[38]. 通过激活AMPK进而抑制mTOR活性, 使肝癌细胞周期停滞于G1期, 随后发生凋亡[39]. 活化的AMPK通过抑制mTOR活性, 使结肠癌细胞发生凋亡[40]. 活化的AMPK可诱导肝癌细胞[41]、结肠癌细胞[42]自噬.
侵袭和转移是恶性肿瘤的重要特征, 侵袭性生长是转移的前提和基础, 转移则是侵袭的继续和发展. 基质金属蛋白酶(matrix metalloproteinases, MMPs)在肿瘤侵袭过程中的作用近年来备受关注, 大量证据表明基质金属蛋白酶与人类多种恶性肿瘤侵袭转移潜能及预后密切相关. Sun等[43]用放射线诱发p53突变, 发现突变型P53可在转录水平激活编码内皮生长因子受体、MMPs和血栓素基因, 从而调节多种转移相关基因的表达. 缺氧诱导因子-1(Hypoxia-inducible factor-1, HIF-1)是一种氧依赖性转录激活因子, 在机体低氧应答中起重要作用. HIF-1能够诱导在血管形成过程中起作用的VEGF等基因表达, 促进新生血管形成, 为瘤细胞侵袭和转移创造条件. 研究表明, 二甲双胍可通过激活AMPK进而抑制HIF-1的表达, 并抑制肿瘤的侵袭和转移[44]. AICAR可通过激活AMPK, 防止肝癌细胞的动物模型发生转移[45]. AMPK与消化系肿瘤的侵袭和转移目前研究较少, 有待进一步的探讨.
血管生成(angiogenesis)是指组织中从既存的成熟血管形成新的毛细血管网络的过程. 肿瘤具有诱导新生血管生成的能力, 其生长和转移都依赖于肿瘤新生血管的生成. 肿瘤新生血管生成过程受血管生成正负调节因子的共同调控, 目前发现的血管生成调节因子主要包括血管内皮细胞生长因子(vascular endothelial growth factor, VEGF)、血管生成素(Angiogenin)、MMPs、血管抑素(Angiostatin)及血小板反应素1(Thrombospondin-1, TSP-1)等数十种. 在糖尿病的相关研究中证实二甲双胍可以通过激活AMPK, 抑制胰岛素和IGF-1诱导的HIF1a和VEGF表达. Tan[46]等在对多囊卵巢综合征的研究证明, 二甲双胍可以通过NF-kB和Erk1/2/Erk5 通路上调抗血管生成因子TSP-1的表达, 进而抑制血管生成. 另有报道指出, 在肝癌细胞中, 活化的AMPK可介导VEGF的表达, 使新血管形成活跃[47]. AMPK与新生血管形成的关系说法不一, 其关系仍需进一步的研究.
AMPK已被证明其对多数人类肿瘤细胞株具有毒性作用, AMPK将可能成为抗肿瘤治疗的新靶点. 其机制十分复杂, 具体机制尚未完全阐明. 目前主要认为是通过HMG-CoA还原酶、ACC、FASN及mTOR直接抑制肿瘤的增殖, 诱导细胞周期停滞及细胞凋亡; 还可通过间接抑制肿瘤的侵袭和转移、血管生成等来抑制肿瘤增殖, 阻止肿瘤进展. 近来有研究发现, 姜黄素可通过AMPK-COX2途径诱导结肠癌细胞凋亡[48,49]. 活性氧(reactive oxygen species, ROS)可通过调节AMPK-NF-κB途径在肝癌细胞增殖受抑制中起重要的作用[50]. 目前AMPK与消化系肿瘤关系的研究主要集中在肝癌、结肠癌等, 而食管癌、胰腺癌、直肠癌及胃癌报道较少. 总的来说, AMPK与消化系肿瘤的关系正处于研究初期, 我们期待更多的AMPK新功能被细致阐明.
近年, 腺苷酸活化蛋白激酶(adenosine monophosphate activated protein kinase, AMPK)与肿瘤关系的研究越来越多. 而AMPK作用于肿瘤的确切机制仍不清楚.
禹正杨, 副主任医师, 副教授, 南华大学附属第一医院消化肿瘤外科; 张俊, 副教授, 上海交通大学医学院附属瑞金医院外科八病区
活化的AMPK可诱导消化系肿瘤细胞凋亡; AMPK还与消化系肿瘤的新生血管形成及侵袭转移等密切相关.
全文综述了AMPK与肿瘤关系的一些研究成果, 有一定的学术参考价值和新颖性.
编辑:张姗姗 电编:闫晋利
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