胆碱激酶α隶属于胆碱激酶蛋白家族。胆碱激酶是一组由CHOKA、CHOKB基因编码的带有胆碱激酶/乙醇胺激酶活性域的酶蛋白,有胆碱激酶α和胆碱激酶β两种亚型[1]。在体内,胆碱激酶β(最初被称为胆碱激酶样分子)仅发挥乙醇胺激酶的作用,而胆碱激酶α则兼具胆碱激酶/乙醇胺激酶双重活性[2]。胆碱激酶α是CDP-胆碱通路的关键酶,通过其胆碱激酶活性,将胆碱磷酸化为磷酸胆碱,参与磷脂酰胆碱(细胞膜的主要磷脂质)合成[3-4]。磷酸胆碱是重要的第二信使分子,高浓度磷酸胆碱已被证实可以作为细胞内第二信使在DNA合成中发挥重要作用,进而促进细胞增殖[5]。因而,胆碱激酶α可以通过磷酸胆碱间接影响哺乳动物细胞的有丝分裂,参与细胞的生理活动[6-7]。近年来相关研究证实胆碱激酶α与肿瘤发生和发展存在一定联系,本文就胆碱激酶α在肿瘤发生中的功能及其在肿瘤诊治中的作用进行了综述。
1 胆碱激酶α在肿瘤中的功能 1.1 胆碱激酶α在肿瘤组织及细胞中的异常表达与活化众多研究证实,胆碱激酶α在肿瘤组织及细胞中呈现异常表达或活化。Ramírez等[8]研究发现,在上皮肿瘤、造血系统及骨肉瘤等12株肿瘤细胞系中,有10株呈现胆碱激酶α表达升高;在43例肺癌、30例结肠癌和31例前列腺癌患者的正常及肿瘤组织中,有56%的肺癌组织、47%的结肠癌组织和48%的前列腺癌组织呈胆碱激酶α的高表达,而其相应正常组织中胆碱激酶α水平均为低表达。该课题组还在多种乳腺癌细胞中检测到胆碱激酶α的过表达及磷酸胆碱水平的升高,而胆碱激酶α抑制剂对乳腺癌细胞移植瘤表现出较强的抗肿瘤活性,提示胆碱激酶α对于肿瘤生长具有重要作用[9]。Nakagami等[10]发现结肠癌组织中磷酸胆碱水平为正常组织的1.5倍,并且结肠癌和腺瘤组织中胆碱激酶α蛋白的表达水平及活性均显著高于其相应正常组织。在二甲基肼诱导的小鼠结肠癌模型中,也观察到胆碱激酶α高表达于癌组织中,且其活性显著升高[11]。在前列腺癌中,胆碱激酶α可被细胞外钙离子激活并参与细胞增殖的维持[12];此外,前列腺癌中低氧诱导因子1α也可诱导胆碱激酶α表达,因此可将胆碱激酶α作为肿瘤缺氧的判断指标[13]。在T细胞淋巴瘤病例中,可见胆碱激酶α表达水平增高及胆碱代谢异常[14]。神经系统施旺细胞的永生化及恶性转化中也表现出磷酸胆碱水平的显著上升[15]。胰腺导管腺癌细胞系及皮下种植瘤中胆碱激酶α均表现为活化水平升高[16]。
胆碱激酶α异常活化在多种肿瘤进展中具有重要意义。针对乳腺癌致瘤细胞株的研究显示,其磷酸胆碱水平显著高于永生化非致瘤细胞株及低致瘤细胞株,提示磷酸胆碱水平会随肿瘤恶性表型的获取而升高[17]。Mori等[18]研究发现胆碱激酶α siRNA可提高乳腺癌细胞对5-氟尿嘧啶的化疗敏感性,而对非恶性乳腺上皮细胞的生存及细胞增殖没有明显影响,说明胆碱激酶α可能参与乳腺癌细胞化疗耐药性的产生。胆碱激酶α过表达可以提高乳腺癌细胞侵袭能力,同时亦可通过提高药物排出泵活性增强乳腺癌细胞的化疗耐药性[19]。在一项53例乳腺癌临床病例的分析中,研究者发现癌组织中胆碱激酶α的活性比正常组织升高38.5%,且与病理分级显著相关,提示胆碱激酶α的活性与乳腺癌进展联系密切[20]。在上皮性卵巢癌细胞系中,抑制胆碱激酶α的表达后肿瘤细胞生长也受到明显抑制,细胞侵袭和迁移能力显著下降,并且对多种化疗药物的耐药性显著减弱[21]。一项针对非小细胞肺癌的回顾性研究提示,胆碱激酶α高表达患者的预后较差[22]。
上述证据充分说明,胆碱激酶α在多种肿瘤中出现异常表达及活化,参与了肿瘤发生、进展及化疗耐药性等肿瘤恶性行为的维持。
1.2 胆碱激酶α与肿瘤相关通路的交叉调控胆碱激酶α与多种肿瘤相关信号通路存在交互作用,其可被多种原癌基因激活。Ras转化细胞中胆碱激酶α的活性显著升高,而胆碱激酶α抑制剂可抑制Ras转化细胞的增殖,表明胆碱激酶α介导Ras依赖的肿瘤发生[23]。相关机制研究逐步证实,Ras原癌基因是通过其效应蛋白Ral-GDS和PI3K调控胆碱激酶α活性的提升[24],继而有效提高磷酸胆碱浓度,从而发挥作用[25]。在肿瘤细胞中,胆碱激酶α通过c-Src依赖途径与表皮生长因子受体(EGFR)形成复合物,并实现Y197和Y333位点磷酸化,介导表皮生长因子(EGF)依赖的细胞增殖[26]。而在原癌基因erbB2转化的乳腺癌细胞中,也伴有胆碱激酶α活性及磷酸胆碱浓度的升高[17]。
同时,胆碱激酶α也参与多种肿瘤相关通路的调控。在生长因子转化细胞中,阻断胆碱激酶α可完全抑制血小板源性生长因子(PDGF)或成纤维细胞生长因子(FGF)介导的raf-1及MAPK激活,表明该激活过程依赖于胆碱激酶α的活化[27]。磷酸胆碱能够与ATP协同作用促进raf-1酶活化进而激活raf-MEK通路[28]。此外,胆碱激酶α也能通过催化Akt分子磷酸化介导激活非PI3K依赖的Akt通路[29]。在卵巢上皮癌细胞中,胆碱激酶α可通过调节细胞内谷胱甘肽/氧化型谷胱甘肽进而增强肿瘤细胞的耐药性[30]。针对HeLa细胞的研究显示,MAPK和PI3K/Akt通路的前馈放大依赖于胆碱激酶α的表达活化[31]。胆碱激酶α能够通过上调细胞周期蛋白D1和D3、下调p107和细胞周期蛋白G2,促进细胞由G1期向S期过渡,这可能也是胆碱激酶α促癌作用的机制之一[32]。亦有报道认为,抑制胆碱激酶α的酶活性并不足以引起细胞死亡,而是导致细胞周期停滞,说明其在肿瘤中的作用方式并不完全依赖于其催化活性[33]。
这些研究说明,胆碱激酶α与肿瘤相关信号通路存在相互作用,其在肿瘤发生、发展中的作用机制可通过多种信号通路实现。
2 胆碱激酶α与肿瘤诊断及预后评估Hara等[34]将组织对11C胆碱的吸收值作为代谢信号,首次提出11C胆碱-PET-CT概念,通过对人体胆碱激酶α的活性测定,结合CT进行分析,可以产生清晰的脑肿瘤影像。在前列腺癌的局部转移的判断中,11C胆碱-PET-CT也具有实际意义[35]。Contractor等[36]研究发现,11C胆碱-PET-CT在判断前列腺癌患者盆腔淋巴结分期及小病灶检测方面较磁共振成像(MRI)具有更高的敏感性及准确性。Chang等[37]证实11C胆碱-PET-CT在恶性前列腺病变的显像方面较T2W/DW MRI具有更高的准确性。有研究认为11C胆碱-PET-CT对于肝细胞癌肝外病灶的诊断较CT/MRI更加准确[38]。在去势难治性转移性前列腺癌患者中,18F-氟代胆碱-PET-CT对恩杂鲁胺的早期反应具有重要评估价值,同时结合前列腺特异性抗原可准确预测患者的无进展生存[39]。18F-氟代胆碱-PET-CT在低分化胶质瘤患者治疗随访中的准确性显著高于aMRI与201Tl-SPECT[40]。
有研究发现采用核磁共振(NMR)技术可对在体组织胆碱激酶α的活性进行准确监测,并有望使之成为一种非侵入性的成像标记物,以用于肿瘤定位诊断[41]。此外,一项基于1HNMR谱的血清代谢组学研究显示,恶性肿瘤浸润性导管癌患者的血清磷酸胆碱水平较乳腺纤维腺瘤患者显著升高,提示该指标有望成为鉴别良恶性肿瘤的血清代谢标记物[42]。针对肺癌的NMR代谢组学研究显示,肺腺癌与鳞癌呈现出不同的磷酸胆碱代谢特征,这对于肺鳞癌与腺癌的鉴别具有参考价值[43]。
在肝细胞癌中,胆碱激酶α的高表达与肿瘤分期显著相关,并预示着死亡率升高[44]。而在非小细胞肺癌中,胆碱激酶α的高表达有助于判断肺癌患者预后及早期患者复发的预测;验证队列中,4年肺癌特异性存活率在胆碱激酶α高表达组中为46.66%,而胆碱激酶α低表达组为67.01%[22]。
但这些手段目前尚未成功推广于临床。针对胆碱激酶α活性的放射学检查虽然具有敏感性高等优点,但胆碱激酶α的表达水平与其活性以及肿瘤组织胆碱摄取能力之间的关系尚需进一步研究证实。
3 胆碱激酶α与肿瘤治疗HC-3是一种较早被证实的胆碱激酶α抑制剂。在原癌基因转化细胞中,HC-3及其衍生物具有较强的生长抑制作用,并且其对生长的抑制作用与其对胆碱激酶α活性的抑制能力相关[45]。Hernández-Alcoceba 等[46]对HC-3的衍生物MN58b等一系列胆碱激酶α抑制剂的研究显示,这类药物对人结肠癌细胞增殖和移植瘤的生长具有显著抑制作用。药物机制研究发现,MN58b和二代HC-3衍生物RSM932A可加剧内质网应激进而触发肿瘤细胞凋亡[47]。此外研究发现,胆碱激酶α小分子拮抗剂CK37也能够有效抑制MAPK和PI3K/AKT通路,且具有选择性抑制肿瘤细胞增殖的特性,并对在体移植瘤的生长也可发挥显著抑制作用[48]。而在T细胞淋巴瘤小鼠种植瘤模型中,CK37可通过抑制Ras-AKT/ERK通路,诱导淋巴瘤细胞程序性凋亡和坏死性凋亡,延缓肿瘤生长速度[14]。近期有研究报道一种近红外荧光羰花青——JAS239,其兼具胆碱激酶α结合特异性和近红外窗荧光获取特性,可同时发挥胆碱激酶α示踪及抑制剂功能,有望成为一种兼具无创性诊断及胆碱激酶α靶向抑制的重要诊疗工具[49]。Rubio-Ruiz等[50]最近也报道了一种非对称二吡啶衍生物作为胆碱激酶α抑制剂在肿瘤治疗中的作用,主要是通过激活Caspase-3诱导肿瘤细胞凋亡。
除化学合成药物外,有研究者报道提取自卫矛科植物的三萜烯醌生物活性物质及其半合成衍生物,在肿瘤细胞及小鼠种植瘤中能通过抑制胆碱激酶α发挥抗肿瘤细胞增殖的作用[51]。
同时,亦有胆碱激酶α特异性siRNA或shRNA抑癌作用的研究报道。Glunde 等[52]报道 RNA干扰介导的胆碱激酶α抑制可诱导乳腺癌细胞分化并抑制细胞增殖,这有助于细胞恶性表型的消除。在小鼠尾静脉注射慢病毒介导的shRNA,可以有效降低胆碱激酶α的表达及活性,进而抑制移植瘤生长[53]。脂质体介导的胆碱激酶α-siRNA 可使乳腺癌细胞系的细胞活性降低40%,小鼠种植瘤体积降低56.5%[54]。
目前,针对胆碱激酶α的靶向治疗尚需完善相关研究,首先其非特异性作用对人体正常细胞的药物毒性有待严格检验;其次在肿瘤细胞中已经发现有耐药性产生[55]。在众多胆碱激酶α抑制剂中,由于对多种肿瘤细胞增殖的抑制作用及有效作用浓度下的低毒性,RSM932A已经获得部分临床前研究证据支持,有望成为第一种进入临床试验的胆碱激酶α靶向药物[56]。
4 小结胆碱激酶α在多种肿瘤组织中呈现高表达及激活状态,并对肿瘤细胞的生存、增殖及恶性表型维持具有关键作用。胆碱激酶α可被多种原癌基因激活,并同多种肿瘤相关信号通路存在交互作用。胆碱激酶α的表达检测、酶活性检测可有效应用于临床,并对肿瘤的早期发现、局部及远处转移、预后判断具有重要意义。靶向抑制胆碱激酶α可以有效抑制肿瘤生长,为肿瘤的治疗提供了一个可能的方向。
目前胆碱激酶α的研究方向将逐渐由细胞实验向在体实验进展,由分子机制向临床应用转化。胆碱激酶α的基础研究仍需继续深入,以期更加明确其详细作用机制;胆碱激酶α用于肿瘤临床诊断的特异性、敏感性仍有待大样本证实;胆碱激酶α靶向治疗的安全性、特异性也有待进一步确认。但不可否认的是,针对胆碱激酶α的检测、治疗将在肿瘤诊治中发挥重要作用。
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