乳腺癌中糖代谢研究进展
Research Progress of Glucose Metabolism in Breast Cancer
DOI: 10.12677/ACM.2023.13122616, PDF, HTML, XML, 下载: 103  浏览: 127 
作者: 董林桓, 张先林:三峡大学附属仁和医院,湖北 宜昌
关键词: 乳腺癌糖原合成糖原合成激酶Breast Cancer Glycogen Synthesis Glycogen Synthesis Kinase
摘要: 乳腺癌仍是女性死亡的主要原因。常规的化疗方式与靶向治疗及免疫治疗的结合能够改善患者的预后,提高患者的生存率。尽管临床试验中都报告出了令人鼓舞的结果,但是仍有许多未解决的一些障碍。这篇综述,将跳过糖代谢作为能量存储方式的一种传统理解,转而去描述糖代谢在肿瘤的生成中所起到的作用,为乳腺癌的发病机制及潜在治疗方式提供新思路。
Abstract: Breast cancer remains the leading cause of death among women. Combining conventional chemo-therapy with targeted therapy and immunotherapy can improve patient prognosis and increase survival rates. Despite encouraging results reported in clinical trials, there are still many unre-solved obstacles. This review aims to move beyond the traditional understanding of sugar metabo-lism as an energy storage mechanism and instead describe its role in tumor formation, providing new insights into the pathogenesis of breast cancer and potential treatment approaches.
文章引用:董林桓, 张先林. 乳腺癌中糖代谢研究进展[J]. 临床医学进展, 2023, 13(12): 18610-18616. https://doi.org/10.12677/ACM.2023.13122616

1. 背景

癌症是全世界范围内人民所面对的主要公众卫生问题之一。目前,乳腺癌仍是美国女性癌症死亡第二大原因 [1] ,也是30至39岁女性中最常见的癌症 [2] 。乳腺癌是一种常见的恶性肿瘤,常常伴随着细胞代谢的异常。早先的研究表明,乳腺癌细胞常常表现出增加的糖合成代谢,以满足其快速生长和生存所需的能量和碳源 [3] [4] 。越来越多的研究发现糖合成代谢在乳腺癌的侵袭和转移中扮演重要的角色,这些代谢产物不仅可以提供额外的能量,还可以作为信号分子激活细胞内的转录因子和信号通路,促进侵袭和转移相关的基因的表达 [5] [6] [7] [8] [9] 。因此,本文将深入讨论糖合成代谢的机制和调控通路,以及针对糖合成相关靶点的治疗策略,为乳腺癌的防治提供新的途径和思路。

2. 糖原合成途径及其与乳腺癌之间的联系

葡萄糖是动物组织中主要的能量底物,它的储存方式是以糖原的形式储存于组织中。糖原(glycogen)是一种由葡萄糖分子组成的聚合物。在糖原合酶(GYS)介导下通过α-1,4-糖苷键(glycosidic)和α-1,6-糖苷键(glycosidic)相互连接。而糖原磷酸化酶(Glycogen phosphorylase, GP)的作用就是破坏α-1,4-糖苷键,生成葡萄糖-1-磷酸(G1P)分子,启动糖原分解 [10] [11] [12] 。

2.1. 糖原合酶(glycogen synthase, GYS)

前文可知,GYS介导糖原的合成,而GYS也被发现为两种亚型,GYS1和GYS2 [13] 。结合蛋白质图谱(https://www.proteinatlas.org/)我们了解到在参与糖原合成的酶中这些都是差异表达的,GYS1主要在骨骼肌和大多数存在糖原的细胞类型中表达,而GYS2仅在肝脏中表达,在非肝肿瘤中的表达量较低甚至没有 [14] 。

较早的学者们认为GYS1是肾癌不良预后的标志物,而 GYS1在大多乳腺癌中也会表达 [14] 、特别是三阴性乳腺癌和Ki67高表达乳腺癌中,敲低GYS1会损害乳腺癌的增殖 [15] 。最近的研究表明这种方式可能是通过NF-κB通路诱导糖原积累并促进肿瘤进展,并且沉默GYS1可以改善舒尼替尼的耐药性 [16] 。

GYS1作为一种潜在的靶向治疗点,早先的研究中发现先天性缺乏GYS1的患者可导致心脏病和心源性猝死 [17] ,最近的研究也越来越重视糖代谢在心脏疾病中的地位 [18] 。综上所述,需要更多的研究去验证GYS1对整个机体所导致的影响,但是相对来说,药物诱导的GYS1抑制所带来的副作用是不及GYS1缺乏的,而GYS1抑制剂的参与也会使得乳腺癌的治疗更有趣。

2.2. 糖原合酶激酶3 (Glycogen Synthase Kinase-3, GSK-3)

1980年由N Embi等人在兔的骨骼肌中发现糖原合酶激酶-3 (GSK-3),并证明其是一种通过磷酸化和灭活GYS来负调节糖原合成的关键酶 [19] 。GSK-3是一种关键的丝氨酸(S)/苏氨酸(T)激酶,参与着体内分化、免疫、代谢、细胞死亡和细胞存活等多种途径。GSK-3在哺乳动物中存在两种亚型:GSK-3α和GSK-3β [20] ,而研究表明,GSK-3β的缺乏会表现出严重肝变性从而导致胚胎期小鼠的死亡,而GSK-3α的缺乏却并不会影响小鼠的健康。并且GSK-3β促进了NF-κB的功能 [21] [22] 。GSK-3β的活性受到多种途径的信号调节:1、GSK3-β活性受磷酸肌醇-3激酶(PI3K)-蛋白激酶B (PKB,也称为Akt)信号调节,激活PI3K会通过PKB/Akt信号通路抑制GSK-3β [9] [23] 。胰岛素、肾上腺等被证明促进Akt的产生,而Akt能将GSK3-β磷酸化,这会导致GSK-3β的失活 [24] [25] 。2、Wnt/β-连环蛋白(β-catenin)信号通路的激活通过抑制GSK-3β阻止其与β-连环蛋白间的相互作用从而使其失活 [25] 。

2.2.1. 乳腺癌中PI3K/Akt/DSK-3β通路

Snail家族的转录因子与胚胎发育和癌症转移期间的EMT相关 [26] [27] 。Snail家族有三个成员编码锌指型转录因子,并被称为Snail (Snail1)、Slug (Snail2)和Smuc (Snail3) [26] 。有研究提出可在乳腺癌细胞中观察到异常的GSK-3β的累积,而在正常或者良性乳腺组织中,却并没有这种发现 [28] 。同时,较早的研究中提出了GSK-3可能是通过抑制细胞转录的方式从而抑制乳腺癌症上皮–间质转移(epithelial-mesenchymal transition, EMT) [29] ,而NF-κB则是EMT的中心介质 [29] [30] 。而后在Nicole M Davis等人的精彩综述中,详细的描述了PI3K/AKT信号通路的激活可以促进乳腺癌的发生及其作用机制 [31] 。包括最近的研究也进一步证明该信号通路激活可促进乳腺癌的增殖与发展,并提出无机焦磷酸酶1 (PPA1)可以激活该通路,磷酸化DSK-3β并维持slug的稳定性,防止其破坏,使得DSK-3β成为潜在的靶向治疗点 [32] 。

mTOR是一种丝氨酸/苏氨酸激酶,mTOR通过与多种伴侣蛋白结合形成两种不同的信号复合物,mTOR复合物1 (mTORC1)和mTOR复合物2 (mTORC2) [33] 。在许多癌症中都可以检测到mTOR活性升高,早先的研究发现mTORC1对雷帕霉素敏感 [34] ,而药物雷帕霉素对其的抑制引起抗癌作用 [35] [36] 。随后的研究发现mTOR的作用是抑制自噬从而促进癌症的增殖和发展,现在越来越多的学者认为mTOR是乳腺癌的一种潜在靶点。使用雷帕霉素可抑制肿瘤细胞的活性,并抑制其增殖。

通常GSK-3β被认为是肿瘤增殖生长的抑制剂,然而却并不尽然,在某些肿瘤类型中(如胰腺癌),抑制GSK-3β可通过NF-κB的方式来促进肿瘤细胞的凋亡 [37] 。最近关于乳腺癌的研究中同样表明使用GSK-3β抑制剂有抗癌作用 [38] [39] [40] [41] [42] ,并能够缓解转移性乳腺癌的耐药性 [41] 。包括在Azoulay-Alfaguter I的研究中发现在乳腺癌细胞中使用GSK-3β抑制剂可以起类似于雷帕霉素的抗癌作用。并表明GSK-3β是mTORC1的正向调节因子 [42] 。一项研究表明GSK-3和AMPK协同磷酸化TSC2抑制mTORC1活性 [43] 。TSC2是结节性硬化综合征(Tuberous Sclerosis Complex, TSC)的基因产物,是mTORC1的关键抑制因子 [44] 。随后的研究中也出现了GSK-3β可以促进乳腺癌生长的情况,但同时也提出GSK-3β下调可通过抑制ATP的生成刺激AMPK的方式促进细胞凋亡 [45] [46] 。

2.2.2. 乳腺癌中的Wnt/GSK-3β/β-连环蛋白信号通路

GSK-3β与轴抑制蛋白AXIN (axis inhibition protein)和肿瘤抑制蛋白APC蛋白(adenomatous polyposis coli protein)形成复合物。这种复合体被称为破坏复合体,可以将β-连环蛋白磷酸化并促进其降解。而Wnt信号通路的激活可以在各种中介因子的帮助下使得GSK-3β受抑制从而失去对β-连环蛋白的抑制性 [47] [48] 。早期的学者们认为Wnt信号传导的中心效应子β-连环蛋白起转录激活剂的作用,Wnt通路的激活突变导致β-连环蛋白维持了活性,从而诱导了人结直肠癌,在癌症的促进与发展中起重要作用 [48] 。

随着人们越来越重视GSK-3β在癌症中所起的作用,越来越多的研究也说明Wnt/GSK-3β/β-连环蛋白信号通路在乳腺癌中起重要作用。早先在乳腺癌的研究中发现可催化丝氨酸生物合成的磷酸质氨基转移酶的蛋白质编码基因PSAT1失活有利于他莫昔芬治疗ER阳性乳腺癌 [49] 。随后的研究发现ER阴性乳腺癌中PSAT1的表达显着上调,而PSAT1通过诱导GSK-3β磷酸化从而维持β-连环蛋白的稳定性从而促进乳腺癌发生 [50] 。包括早先的研究中曾提出β-连环蛋白信号传导可以上调细胞周期蛋白D1 (cyclin-D1)基因的转录 [51] 。同时,也有研究提出GSK-3β可以直接通过磷酸化抑制细胞周期蛋白D1的表达 [50] [52] ,从而抑制其在乳腺癌中的致癌性 [53] 。

早先的认知中认为肥胖与乳腺癌风险相关 [54] ,并提出胰岛素抵抗与众多肿瘤的发生发展相关。基于这种前瞻性想法,Mantzoros C等人通过统计方式得出结论:低血清脂联素(Adiponectin)可能通过其介导的胰岛素增敏的抑制这种方式促进乳腺癌组织的生长 [55] 。随后的后续研究发现脂联素不仅可以防止Akt诱导的GSK 3β磷酸化,而且可以通过GSK 3β/β-连环蛋白信号通路,降低细胞周期蛋白D1的表达,减少雌性裸鼠乳腺肿瘤的发生 [56] 。

Figure 1. The mechanism of GSK-3β in breast cancer formation

图1. GSK-3β在乳腺癌形成中作用机制

所以GSK-3β在乳腺癌的形成及进展中的作用颇具争议(图1)。大多数情况下,GSK-3β表现出抑制乳腺肿瘤的增殖生长。然而随着研究的深入,发现GSK-3β抑制剂同样能抑制乳腺癌的生长 [37] - [42] ,GSK-3β抑制剂也可以增加癌症对放射和化学的敏感性 [8] [41] 。同时,在不同的肿瘤中,GSK-3β的表现也不近相同,换而言之,有研究表明诸如胰腺癌与乳腺癌均可观察及异常的GSK-3β核累积,而这里GSK-3β可能是通过激活NF-κB抑制细胞凋亡的作用 [8] [28] [32] 。这也和我们发现的GSK-3β抑制癌症生长的功能相违背,然而GSK-3β是如何激活NF-κB的具体机制还不清楚,包括GSK-3β是如何进入细胞核从而导致异常核累积的方式也未明确,这都是未来需要解决的地方。

3. 讨论

乳腺癌作为女性死亡的主要原因之一,其治疗方式包括常规化疗、靶向治疗和免疫治疗的结合,已经在一定程度上改善了患者的预后和生存率。然而,仍存在一些未解决的难题。本文综述了糖代谢在乳腺癌发生发展中的作用,为乳腺癌的发病机制和潜在治疗提供了新的思路。

糖代谢是乳腺癌细胞快速生长和存活所需能量和碳源的重要途径。过去的研究表明,在乳腺癌细胞中存在增加的糖合成代谢。这些代谢产物不仅提供额外的能量,还作为信号分子激活细胞内的转录因子和信号通路,促进侵袭和转移相关基因的表达。糖原合酶(GYS)是糖原的合成关键酶,其不同亚型GYS1和GYS2在乳腺癌中的表达差异也被观察到。研究发现GYS1在乳腺癌中高表达,并与不良预后和增殖相关。GYS2主要在肝脏中表达,而在非肝肿瘤中的表达较低甚至没有。GYS1的抑制可能成为乳腺癌治疗的潜在靶点。

糖原合酶激酶3 (Glycogen Synthase Kinase-3, GSK-3)是另一个在乳腺癌中引起关注的酶。GSK-3β参与多种途径的调节,包括PI3K/Akt/GSK-3β通路和Wnt/GSK-3β/β-连环蛋白信号通路。研究发现GSK-3β的活性调节与乳腺癌的增殖和发展密切相关。然而,GSK-3β在不同肿瘤中的作用可能不同,有时表现为抑制肿瘤生长,有时则促进肿瘤生长。此外,mTOR和NF-κB等信号通路也与乳腺癌的糖代谢和增殖相关。

综上所述,糖代谢在乳腺癌的发生和发展中起着重要的作用。糖原合酶和GSK-3β是糖代谢关键调节因子,其活性和调控对乳腺癌的增殖和转移具有重要影响。进一步研究糖代谢调控机制和相关信号通路,将为乳腺癌的治疗提供新的靶向治疗策略,为患者的预后和生存率带来新的希望。未来的研究需要进一步阐明这些关键酶和通路在乳腺癌中作用的具体机制,并寻找更有效的治疗策略。

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