修回日期: 2014-11-08
接受日期: 2014-11-18
在线出版日期: 2015-01-08
胃癌是最常见的恶性肿瘤之一. 外科手术是本病的主要治疗方法. 虽然外科手术已取得了一定进展, 但对于胃癌复发明显增加的患者来说总体生存率改善甚微. 尽管新药物的开发已显著提高胃癌化疗的效果, 但病灶不能切除或转移性胃癌的患者预后仍较差. 因此, 有必要找出一些有效针对胃癌的新方法. 现已证明自噬在胃癌的转化和进展扮演双重角色: 自噬的激活和诱导均可导致胃癌的发生. 最近, 一些自噬分子靶向药物治疗胃癌进行了研究. 本文综述了两种调控细胞自噬方法来互补治疗胃癌: 抑制剂和诱导剂, 并讨论他们如何调控自噬靶向治疗胃癌.
核心提示: 胃癌的治疗除了手术及放化疗之外, 还可通过自噬调控的抑制剂可打破自噬对于胃癌的保护作用及其诱导剂增强胃癌细胞的代谢毒性来互补治疗胃癌.
引文著录: 张方信, 王彬彬, 武承凤, 郑晓凤, 马强. 胃癌自噬靶向治疗的研究进展. 世界华人消化杂志 2015; 23(1): 51-57
Revised: November 8, 2014
Accepted: November 18, 2014
Published online: January 8, 2015
Gastric cancer is one of the most common malignant neoplasms. Surgery represents the main approach for this disease. Notwithstanding the advances in surgical techniques, there has been still a minimal improvement in overall survival with a significant increase in relapse rates. Although the development of new drugs has significantly improved the effectiveness of chemotherapy, the prognosis of patients with unresectable or metastatic gastric carcinoma remains poor. Therefore, it is necessary to find some new ways against gastric carcinogenesis. It has been shown that autophagy plays a dual role in the transformation and progression of gastric cancer; activation and induction of autophagy can lead to gastric carcinogenesis. Recently, several agents targeting autophagy molecules in gastric carcinogenesis have been investigated. This article reviews the regulation of autophagy with inhibitors or inducers to treat gastric cancer, and discusses how they regulate autophagy as a targeted therapy for gastric cancer.
- Citation: Zhang FX, Wang BB, Wu CF, Zheng XF, Ma Q. Targeting autophagy for therapy of gastric cancer. Shijie Huaren Xiaohua Zazhi 2015; 23(1): 51-57
- URL: https://www.wjgnet.com/1009-3079/full/v23/i1/51.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i1.51
自噬是一种通过降解受损的细胞器和蛋白质的代谢途径, 产生一定的能量以维护内环境的稳定; 他是指非选择性降解过程巨自噬, 其他形式的自噬包括微自噬和分子伴侣介导的自噬. 自噬在肿瘤的作用存在争议, 目前还未完全阐明. 肿瘤微环境是缺氧和较差的营养物质, 自噬作用可能有助于肿瘤细胞以适应变化的条件, 从而防止其凋亡, 而自噬作用的压力过重或时间太长, 可成为细胞毒性进而导致细胞死亡[1,2]. 激素治疗、多重化疗、放射治疗和一些有针对性的治疗通过诱导增强自噬来治疗不同类型的肿瘤[2-5]. 但在治疗过程中也出现了生存优势的癌细胞, 自噬干扰是比较合理的治疗策略[6,7]. 自噬调控剂可以抵消双重作用以提高抗肿瘤的效果. 本文通过介绍自噬调控剂作为靶向治疗胃癌策略, 希望能对胃癌的预防和诊治提供新的途径.
自噬分子机制依赖于庞大复杂的信号通路网, 可分解成几个阶段, 但详细机制尚未完全阐明[8]. 自噬囊泡起始、延伸、成熟和物质降解的各个阶段都需要一系列多种自噬相关蛋白(autophagy-related proteins, ATG)的参与; 起始阶段通过抑制雷帕霉素靶点受体(mechanistic target of rapamycin, mTOR)触发Unc51-样激酶(Unc51-like kinase, ULK)复合物(包括ULK1/2、ATG13和ATG101)从细胞质向内质网易位; 抑制mTOR使ULK复合物去磷酸化, 激活200 kDa相互作用蛋白家族(family interacting protein of 200 kDa, FIP200)-ATG13-ULK复合物, 形成一个将自噬信号整合到自噬体的节点; 接着, 磷脂酰肌醇-3-激酶(phosphatidylinositol 3-kinases, PI3K)复合物[包括液泡分选蛋白(vacuolar protein sorting, VPS)34、VPS15、Beclin 1及ATG14]、双FYVE包含蛋白1(double FYVE-containing protein 1, DFCP1)和WD重复结构域磷酸肌醇交互(WD-repeat domain phosphoinositide-interacting, WIPI)家族蛋白也被聚集到向内质网; 自噬泡的延伸和闭合需要ATG12-ATG5-ATG16L1和ATG7-ATG3-ATG8-微管相关蛋白轻链3(microtubule-associated protein light chain 3, MAPLC3)-磷脂(phosphatidylethanolamine, PE)复合物的参与; 细胞质中的LC3称为LC3-Ⅰ; ATG5-ATG12-ATG16L1复合物促使自噬囊泡伸长后, LC3缀合到膜的内外侧, 被称为LC3-Ⅱ. 伸长的后期, ATG5-ATG12-ATG16L复合物从自噬囊泡上解离, 最终形成闭合成熟的双膜结构, 称为自噬体; 相比之下, LC3参与整个自噬体形成的过程, 广泛用于哺乳动物细胞中自噬的监测; 最后, 在自噬体与溶酶体对接和融合, 形成自噬溶酶体, 最终将包裹的物质降解成小分子物质被循环利用[8-12].
在应激条件下, 自噬是一种进化上保守的作用, 通过调节代谢促进细胞存活. 这激发了研究自噬作用是否可促进细胞毒性来治疗耐药性. 抑制自噬可阻止其作为生存机制的使用, 可能激活凋亡信号, 推动细胞进入凋亡[13]. 干扰自噬可通过多个途径调制来实现自噬靶向治疗肿瘤, 主要通过ATGs的敲出或抑制药物抑制. 自噬抑制剂有溶酶体抑制剂氯喹与羟氯喹、PI3K抑制剂3-甲基腺嘌呤(3-methyladenine, 3-MA)和导致辅酶烟酰胺腺嘌呤二核苷酸耗竭的化合物FK866[14-16]. 超活化细胞自噬的能量可导致肿瘤细胞成自噬性死亡, 后者不同于细胞凋亡, 是胱天蛋白酶非依赖性的死亡, 与自噬体的形成增加相关联[17]. 而自噬诱导剂包括mTOR抑制剂、磷酸腺苷活化蛋白激酶(adenosine monophosphate-activated protein kinase, AMPK)诱导剂等[18,19]. 目前, 自噬相关的药物主要用于实验研究, 用于临床疾病治疗的甚少.
氯喹是一种常用的自噬抑制剂, 其机制主要是通过改变溶酶体的pH值, 并阻断自噬小体与溶酶体的融合从而导致自噬小体聚集[20]. 氯喹作为新型的抗肿瘤药物已用于治疗乳腺癌、宫颈癌等多种肿瘤, 且与化疗药物联合增强肿瘤的杀伤能力[14,21]. Zhang等[22]研究自噬对于顺铂诱导胃癌凋亡的机制发现, 通过氯喹抑制自噬后, 细胞凋亡率、Caspase3和P53蛋白的蛋白表达水平明显增加, 而Bcl-2蛋白表达减少. 自噬防止顺铂诱导胃癌细胞凋亡, 形成保护性机制, 而抑制自噬能促进细胞凋亡. 因此自噬抑制剂氯喹并联合顺铂治疗胃癌可能是一种很有前途的治疗策略.
3-MA是一种自噬抑制剂, 主要通过抑制PI3K, 减少磷脂酰肌醇3-磷酸的生成, 进而抑制隔离膜或自噬小泡招募ATG的合成. 最近研究[23]证实, 3-MA通过抑制自噬增强胃癌细胞的凋亡. Li等[24]研究发现, 苦参碱诱导胃癌细胞产生保护性自噬; 但联合自噬抑制剂3-MA可通过细胞凋亡途径增强苦参碱对肿瘤细胞的杀伤力. Humbert等[25]研究发现, 在胃癌细胞株GTL-16过度表达MET, 而MET抑制剂PHA665752和EMD1214063通过抑制自噬导致胃癌细胞死亡; MET抑制剂联合自噬抑制剂3-MA或敲除自噬基因ATG7可进一步降低胃癌细胞的细胞活力. Liu等[26]研究表明, β-榄香烯通过诱导自噬的保护, 防止人胃癌细胞发生凋亡, 但β-榄香烯联合自噬抑制剂3-MA, 或敲除自噬基因Beclin-1, 可显著增强β-榄香烯的抗肿瘤效果. 这些数据表明, 抗癌药物激活肿瘤细胞适应应激条件的自噬以保护细胞免于死亡, 可联合自噬抑制剂3-MA增强肿瘤细胞的杀伤力.
2.2.1 mTOR抑制剂: mTOR的抑制剂通过激活ULK复合物诱导自噬的发生. 雷帕霉素作为mTOR抑制剂主要通过抑制移植瘤血管的生成而发挥抗肿瘤的作用[27], 并能降低小鼠人肺癌模型肿瘤的复发[28]. mTOR抑制剂逐渐作为新型抗肿瘤药物用于各种肿瘤的治疗.
胃癌晚期患者常常伴有腹膜转移, 经过任何治疗依然预后不佳, 目前已知趋化因子在肿瘤生长和转移发挥重要作用. Hashimoto等[29]研究发现, 趋化因子CXCL12在腹膜转移的胃癌组织中的发生发展中具有重要作用; 这项研究中, 腹膜转移癌信号途径通过趋化因子CXCL12其受体CXCR4相互作用, 诱导AKT迅速磷酸化, 激活mTOR途径抑制细胞自噬, 产生大量基质金属蛋白酶(matrix metalloproteinases, MMP), 最终促进胃癌细胞腹膜转移及生长, 而mTOR特异性抑制剂雷帕霉素可明显抑制胃癌细胞转移并诱导细胞发生自噬性细胞死亡. 另外, 雷帕霉素也抑制决定癌细胞侵袭的驱动力的MMP的生产, 并通过自噬作用引发的细胞死亡. Yu等[30]通过1072例胃癌患者免疫组织化学染色和蛋白免疫印迹方法研究发现, 总mTOR和磷酸化mTOR的过表达率分别是50.8%(545/1072)和46.5%(499/1072), 磷酸化mTOR的表达比总mTOR更有意义; 总mTOR与肿瘤大小及疾病所处状态有关, 而磷酸化mTOR则与淋巴结转移和胃癌细胞血管表型生成密切相关, 并且他还可以作为胃癌患者预后的独立因子. 因此, 雷帕霉素阻止mTOR信号通路可能是腹膜播散性胃癌的一种治疗方法.
依维莫司(everolimus, RAD001)是mTOR的一种变构抑制剂, 已经证实具有抗肿瘤活性, 用于多种肿瘤的治疗, 包括结节性硬化症相关的肾细胞癌、乳腺癌、胰腺神经内分泌肿瘤和胶质母细胞瘤等[31-34]. 依维莫司在抑制mTOR信号的同时可导致Akt激活, 联合Akt的抑制剂MK-2206增强抗肿瘤的功能[35]. Ji等[36]研究发现, 依维莫司和MK-2206的组合通过增强Akt/mTOR的抑制效应, 激活有丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)/ERK信号通路介导的自噬途径, 并通过下调周期蛋白D1来增强人第10号染色体缺失的磷酸酶张力蛋白同源基因(phosphatase and tensin homologue deleted from chromosome 10, PTEN)突变型胃癌细胞的抗肿瘤活性. Xu等[37]研究发现, 依维莫司通过下调p70s6k和磷酸化的p70s6k的表达促进癌细胞自噬, 并上调p53的表达抑制胃癌细胞逃逸细胞周期, 从而抑制胃癌细胞的增长. 由此可以推测依维莫司通过可能抑制mTOR途径抑制胃癌细胞的增殖, 但是其中的详细机制尚不完全明确, 需要进一步深入研究.
E铂(E platinum)是一种新合成的铂类抗肿瘤药物, 但抗肿瘤的详细机制尚不明确. 近来一些研究发现他参与细胞自噬的相关调控过程来杀死癌细胞. Hu等[38]研究发现, E铂处理的胃癌细胞胞质中发现大自噬泡积累, 而且水溶性的LC3-Ⅰ向脂溶性的LC3-Ⅱ转化, 自噬相关蛋白Beclin-1的表达也增加了; 此外, 用3-MA、氯喹和RNA干扰下调LC3和Beclin-1的表达抑制细胞自噬, 可增强胃癌细胞的杀伤性; 该研究进一步探索了E铂可能参与自噬的信号通路, E铂通过抑制mTOR和p70S6K的活化, 减少Akt、ERK1/2、JNK和p38的磷酸化, 阻断MAPK信号传导致使自噬激活, 抑制胃癌细胞的生长. 因此, E铂可作为一个有前途的具有诱导自噬参与的抗肿瘤药物, 但是其介导与mTOR连接相关激酶的活化仍有待于阐明, 这一发现提供了E铂治疗癌细胞新的见解.
2.2.2 AMPK诱导剂: AMPK是丝氨酸/苏氨酸蛋白激酶的家族性激酶, 他能致敏细胞应激, 调节代谢和细胞增殖[39]. 在应激条件下, 细胞通过AMPK/mTOR信号通路调控自噬, 激活自噬启动激酶导致细胞死亡[40].
替加环素(tigecycline)作为一种甘氨酰四环素类抑菌剂, 抵抗一系列的细菌, 特别是耐药细菌. 越来越多的证据表明, 四环素和其如多西环素和米诺环素衍生物具有抗癌性质[41]. Tang等[42]研究发现, 替加环素通过诱导的自噬而不是凋亡显著抑制胃癌细胞增殖. 用替加环素干预体外胃癌细胞后, AMPK信号通路被激活, 进一步抑制mTOR的磷酸化, 通过调节下游效应因子p70S6K的磷酸化, 最终诱导细胞自噬并抑制细胞的生长, 这是替加环素涉及自噬诱导传感途径之一; 另外, 他们还用人胃癌细胞转移瘤小鼠模型进一步证实替加环素能够抑制肿瘤的生长. 因此, 替加环素通过AMPK/mTOR信号通路诱导自噬抑制肿瘤生长的策略为胃癌患者的治疗提供了新线索.
木通皂苷PA(akebia saponin PA, AS)是一种从续断分离出来的天然产物, 具有抗氧化、抗炎和骨保护等作用[43-45]. 最近一项研究[46]发现, AS能够诱导胃癌细胞死亡, 其机制可能是通过诱导细胞自噬和凋亡的双重作用; AS通过激活AMPK/mTOR信号转导通路诱导自噬性死亡; 同时还发现, AS通过激活MAPK信号通路促进Caspase3依赖性凋亡的发生, 这些结果表明, 天然存在的化合物AS诱导自噬和凋亡发挥抗肿瘤的作用.
2.2.3 核因子-κB(nuclear factor-kappa B, NF-κB)抑制剂: NF-κB是一类具有多向转录调节作用的核蛋白因子, 存在于多种组织的多种细胞中, 具有广泛的生物学活性, 激活后参与许多基因的转录调控. 近年来的研究表明NF-κB与细胞凋亡和自噬的关系密切, 在肿瘤的发生发展中发挥着重要作用[47].
SN50作为可抑制NF-κB的核转运导致细胞死. Zhu等[48]研究发现, SN50通过上调LC3、Beclin-1和P53蛋白表达抑制胃癌细胞的增殖; 而p53抑制剂PFT-α可阻断SN50抑制LC3和Beclin-1的表达, 进一步证明在抑制NF-κB的条件下, p53可激活细胞自噬和凋亡; 这项研究阐明了NF-κB抑制剂抗肿瘤分子机制的新亮点, 深入研究NF-κB抑制剂、自噬活化与细胞凋亡三者之间抗肿瘤的关系, 为胃癌的治疗推出新策略.
姜黄素(curcumin)是从姜科姜黄属植物姜黄根茎中提取的一种酚性色素, 属于天然酚类抗氧化剂, 具有多种药理功效, 如抗氧化、消炎、抗肿瘤等作用. 邓淑文等[49]研究发现, 姜黄素对人胃癌细胞胞增殖具有抑制作用, 主要通过上调Beclin-1/LC3-Ⅱ水平调控并诱导癌细胞发生自噬, 同时发现NF-κB的表达也增高. 而现在又发现NF-κB具有促进细胞凋亡的作用, 可能也参与了自噬调控的细胞凋亡. 因此, 该研究为姜黄素用于临床肿瘤的治疗提供了一个新的依据, 但与自噬和NF-κB之间的详细机制仍需要进一步研究.
2.2.4 环氧化酶抑制剂: 塞来昔布(celecoxib)属于选择性抑制环氧化酶-2(cyclooxygenase-2, COX-2)的非甾体类抗炎药, 此药在临床上既用于治疗骨关节炎和关节风湿疼痛缓解, 又用于家族性腺瘤性息肉病患者的化疗[50,51]. 塞来昔布在几种肿瘤模型中的主要机制包括诱导细胞周期停滞, 细胞线粒体介导的通路, 内质网应激和自噬, 但在胃癌细胞中的详细作用与机制还没有得到充分的探讨[52-55]. Liu等[56]研究发现, 塞来昔布可能参与抑制PI3K/Akt信号通路同时诱导胃癌细胞的凋亡和自噬, 用塞来昔布处理的细胞可发现自噬小体和凋亡小体同时存在, 并且Caspase8和Caspase9的信使RNA表达随时间和剂量显著增加, 而Akt的信使RNA表达则降低. 这些结果表明, 塞来昔布通过PI3K/Akt信号途径诱发胃癌细胞自噬和凋亡的发生. 这项研究的结果提供了塞来昔布抗肿瘤机制的新的理论基础, 并提供了治疗癌症的新目标, 虽然这些研究结果应该在今后的调查核实但是塞来昔布诱导细胞自噬和凋亡的具体机制以及凋亡与自噬之间的联系并未完全阐明, 今后仍需深入研究.
自噬调节可以通过多层次多路径的干扰来实现. 因此, 自噬调节特性的化合物的数量是巨大的, 而且这些不同化合物之间相互作用是不同的. 由于肿瘤微环境的复杂性, 目前自噬调控剂对于肿瘤的治疗大多处于基础研究水平, 并且对于患者来说, 自噬水平的测量难度大, 因此自噬调节剂尚未进入临床病例研究. 并且自噬靶向治疗胃癌刚刚起步, 有待于进一步探索自噬靶向治疗胃癌详细情况, 最终促进胃癌治疗新方法的诞生.
目前胃癌的各种治疗都不尽如人意, 尤其中晚期胃癌患者的疗效及预后不容乐观, 尽管最近一些新的治疗方案已经推出, 但是个体间的变异反应和耐药性仍然是一个挑战, 寻求一种新方法治疗胃癌是目前研究的重中之重. 自噬是细胞维持内环境稳定的一种代谢过程. 自噬在胃癌中的角色很复杂, 自噬可能促进或抑制胃癌细胞死亡. 因此, 如何调控自噬治疗胃癌是目前研究的重点, 以提高胃癌的治疗.
郭俊明, 教授, 宁波大学医学院生物化学与分子生物学研究所
近年来, 人们在肿瘤、炎症、应激等损伤的调控途径中均发现自噬现象, 其调控的分子机制过程极其复杂, 如何通过自噬相关调控机制治疗相关疾病值得深入研究.
Nagelkerke等系统地总结了自噬的分子机制及自噬靶向治疗肿瘤的药理机制.
本文比较系统地总结了自噬抑制剂和诱导剂靶向治疗胃癌的相关分子靶点及药理机制, 但是目前的自噬调控治疗处于实验阶段, 临床应用的相对很少, 需要更进一步研究.
通过研制各种自噬抑制剂或诱导制剂, 为胃癌的靶向治疗提供新策略.
本文综述了抑制剂和诱导剂调控细胞自噬方法来互补治疗胃癌, 对我们了解细胞自噬与胃癌治疗有一定帮助.
编辑:郭鹏 电编:都珍珍
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