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World Journal of Cancer Research
Vol. 12  No. 03 ( 2022 ), Article ID: 54232 , 5 pages
10.12677/WJCR.2022.123027

PI3K/AKT/mTOR通路在卵巢癌中的作用

张乐¹，张燕¹，李红霞2*

1延安大学医学院，陕西 延安

2延安大学附属医院妇科，陕西 延安

收稿日期：2022年7月5日；录用日期：2022年7月16日；发布日期：2022年7月29日

摘要

卵巢癌是所有妇科恶性肿瘤的主要死亡原因。在卵巢癌的发生过程中，异常信号通路的激活必不可少。PI3K/AKT/mTOR通路的激活存在于多种恶性肿瘤的演变过程中，控制细胞周期、代谢、粘附。近年来，通过研究PI3K/AKT/mTOR通路的机制及靶向抑制剂，从而为恶性肿瘤的靶向治疗奠定基础已成为学术界的热点。本文就该信号通路在卵巢癌中可能发挥的作用做一综述。

关键词

卵巢癌，PI3K/AKT/mTOR信号通路，靶向治疗

The Role of PI3K/Akt/mTOR Pathway in Ovarian Cancer

Le Zhang1, Yan Zhang1, Hongxia Li2*

1Medical School of Yan’an University, Yan’an Shaanxi

2Department of Gynecology, Affiliated Hospital of Yan’an University, Yan’an Shaanxi

Received: Jul. 5th, 2022; accepted: Jul. 16th, 2022; published: Jul. 29th, 2022

ABSTRACT

Ovarian cancer is the main cause of death of all gynecological malignancies. In the process of ovarian cancer, the activation of abnormal signal pathway is essential. The activation of PI3K/Akt/ mTOR pathway exists in the evolution of a variety of malignant tumors and controls cell cycle, metabolism and adhesion. In recent years, it has become a hot spot in academic circles to study the mechanism of PI3K/Akt/mTOR pathway and targeted inhibitors, so as to lay the foundation for targeted therapy of malignant tumors. This paper reviews the possible role of signaling pathway in ovarian cancer.

Keywords:Ovarian Cancer, PI3K/Akt/mTOR Signal Pathway, Targeted Therapy

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

卵巢癌(Ovarian Cancer)是所有妇科恶性肿瘤的主要死亡原因 [1]，三分之二的患者在诊断时处于晚期，估计的5年生存率为20%~40% [2]，尽管进行了积极的减瘤手术和辅助或新辅助化疗，但70%~80%的预后不良和高死亡率患者仍会出现复发。此外，耐药或复发性疾病的二线治疗选择有限 [3] [4]。因此，了解促进疾病进展、复发和化学耐药性的最常改变的途径，寻找潜在的候选药物(作为单药或联合疗法)或提高目前可用的针对卵巢癌的化疗方案的治疗效果尤为重要。有研究表明，PI3K/AKT/mTOR通路的激活是导致卵巢癌细胞具有更高侵袭性和迁移能力的关键机制 [5]。本文就该信号通路在卵巢癌中可能发挥的作用做一综述。

2. PI3K/AKT/mTOR信号通路概述

PI3K/AKT/mTOR信号通路主要由PI3K、AKT、mTOR组成。PI3K蛋白是由催化p110亚基(PIK3CA)和调节性p85亚基(PIK3R)组成的异源二聚体，介导酶的受体结合，激活和定位。该通路还集成了许多上游输入，包括生长因子(表皮生长因子，肿瘤生长因子等)，酪氨酸激酶受体(胰岛素生长因子1受体，表皮生长因子受体，HER2)和其他膜受体，如Met，或RAS介导的与Ras-Raf-Mek-Erk途径31的串扰。上述化合物与PI3K的相互作用激活下游效应子，如AKT和mTORC1复合物 [6] [7]。Akt是一种丝氨酸苏氨酸激酶，可调节大量下游靶标(如Bcl-2相关死亡启动子、GSK-3β、3-catenin、p21、p27、MDM2或叉头框转录蛋白等)，通过促进肿瘤细胞增殖、抑制肿瘤细胞凋亡、调节肿瘤细胞自噬、调节炎症及肿瘤微环境等机制，最终控制关键的细胞存活和代谢过程 [8]。AKT有三种亚型：AKT1、AKT2和AKT3，其中AKT3可以调节卵巢癌细胞中的血管内皮生长因子和血管生成 [9] [10]。雷帕霉素的哺乳动物靶标mTOR是磷脂酰肌醇3-激酶(PI3K)-AKT轴下游的丝氨酸–苏氨酸蛋白激酶。mTOR允许癌细胞逃离正常的生化系统，并调节细胞凋亡和存活之间的平衡 [11]。mTOR复合物由两个组分组成：mTORC1-Raptor复合物和mTORC2-Rictor复合物，其中，mTORC1对雷帕霉素的抑制敏感，而mTORC2则不敏感。此外，mTORC2对Akt施加正反馈激活 [6]。此外，对TCGA数据的分析表明，mTOR的高表达与晚期卵巢癌患者的生存率低有关 [12]。

3. PI3K/AKT/mTOR信号通路对卵巢癌肿瘤发生、增殖和粘附的影响

PI3K/AKT/mTOR信号通路是正常和癌细胞生理学的中枢调节因子，在许多人类癌症中都会改变 [13] [14]。它控制细胞周期、代谢、粘附、细胞存活、运动性、化学耐受性、血管生成和基因组不稳定性 [15]。据估计，这种信号通路在70%的卵巢癌中被激活，以多种方式包括PIK3R1/2突变，PIK3CA的功能获得突变扩增，AKT1/2/3的突变或扩增，肿瘤抑制因子(TSC或LKB1)的丢失或失活突变以及PTEN在癌症发病机制中的丢失或突变、多功能细胞因子TGF-β参与细胞增殖，分化，凋亡和致癌作用 [16]。此外，恶性肿瘤细胞的一个基本生物学特征就是具有改变其黏附于其它细胞和细胞外基质的能力 [17]。这个特性使得肿瘤细胞可以脱离原发生长部位侵袭到周围组织进而形成转移。卵巢癌中恶性腹水在卵巢癌早期阶段可能通过调节正常细胞和癌细胞之间的前粘附相互作用，为卵巢癌的转移做出贡献 [18]。CD44是一类体内分布极为广泛的细胞表面跨膜糖蛋白，可与多种配体结合介导细胞与细胞、细胞与细胞外基质的相互黏附。CD44标准体(standard isoform of CD44 CD44s)及其剪接变异体(variant isoform of CD44 CD44v)在肿瘤的发生、发展中起重要作用。尤其是CD44v6在肿瘤浸润、转移和预后判定中的作用越来越引起人们的重视 [19]。黄丽珊等研究表明CD44v6表达上调促进肿瘤细胞的迁移从而参与卵巢上皮性肿瘤的恶性演进 [20]。Xiaoqiang Si等研究表明，细胞粘附分子1 (CADM1)的过表达通过调节上游调节剂(LXR/RXR，IGF1，IFI44L和C4BPA)和下游效应子(APP，EDN1，TGFBI和Rap1A)抑制PI3K/Akt/mTOR信号通路，可能抑制卵巢癌细胞的迁移和侵袭 [21]。

4. 卵巢癌靶向治疗中的PI3K/AKT/mTOR通路

PI3K/AKT/mTOR通路因其频繁激活及其在包括卵巢癌在内的许多人类恶性肿瘤中的关键作用而成为一个有吸引力的靶标 [22] [23]。PI3K/AKT/mTOR通路抑制剂可分为4大类：纯PI3K抑制剂、AKT抑制剂、mTOR抑制剂和双mTOR/PI3K抑制剂 [24] [25]。

其中PI3K抑制剂包括BKM120、XL147、GDC0941和PX866。靶向AKT的药物包括AZD5363和GSK2141795，两者都是有效的泛AKT抑制剂 [26]。在PI3K/Akt/mTOR抑制剂中，mTOR抑制剂研究最为广泛。依维莫司在复发性EC中作为单一药物或与来曲唑联合使用在复发性EC中显示出疗效和可接受的耐受性，经FDA批准用于晚期卵巢癌 [27]。双PI3K/mTOR抑制剂PKI-402激活自噬，并通过SKOV3卵巢癌细胞中的自噬和蛋白酶体途径诱导Mcl-1降解，破坏了Bcl-2家族蛋白的平衡，从而抑制细胞增殖并诱导癌症细胞凋亡 [28]。PI3K/AKT/mTORC1途径抑制剂作为治疗卵巢癌的新靶向疗法，I期和II期试验的初步结果令人鼓舞，鼓励进一步研究。然而，目前还没有关于卵巢癌患者的III期试验的报道 [29]。

近年来，针对该通路其他药物的研究比比皆是。Liu等研究表明，葫芦素-A在卵巢癌细胞系SKOV3中诱导细胞周期停滞，凋亡和抑制mTOR/PI3K/Akt信号通路，从而发挥抗癌作用 [30]。张素贤等研究表明，血根碱通过调节PI3K/AKT/mTOR途径，可能在上皮性卵巢癌细胞中表现出抗肿瘤作用，可作为上皮性卵巢癌的潜在治疗试剂 [31]。Zhang等研究提示，马氏体提取物(MTE)抑制SKOV3细胞增殖并诱导其凋亡。PI3K/AKT/mTOR通路的抑制可能会增强MTE的保护作用。因此，MTE可能有望成为治愈卵巢癌的新药 [32]。此外，联合方法现在是一种既定的抗癌策略，Yalikun等研究表明，姜黄素和白藜芦醇联合顺铂治疗对PI3K/AKT/mTOR信号蛋白表达和上皮–间充质转化/肿瘤干细胞表型的影响与对照组相比，单独顺铂治疗后，EOC顺式细胞系中p-AKT、p-mTOR和p-4EBP1的表达水平显著升高。然而，顺铂与姜黄素和白藜芦醇的联合治疗消除了这种变化。姜黄素和白藜芦醇的联合治疗(姜黄素和白藜芦醇分别使用30 µM和70 µM的剂量率)不仅逆转了EOC-cis细胞的EMT表型，而且消除了顺铂诱导的干细胞增强，这些结果表明，姜黄素和白藜芦醇通过逆转EMT和CSC表型，使EOC顺式细胞对顺铂敏感，从而通过显着抑制PI3K/AKT/mTOR途径来抑制卵巢癌细胞中的化学耐药性 [5]。

综上所述，大量研究证明了PI3K/AKT/mTOR通路对卵巢癌增殖、侵袭、转移、进展和化学抗性的重大贡献，尽管目前关于PI3K/AKT/mTOR通路抑制剂在卵巢癌治疗方面仍有较多问题需要解决。随着对治疗的不断研究与探索，针对PI3K/AKT/mTOR通路抑制剂的治疗将取得更大突破。

文章引用

张 乐,张 燕,李红霞. PI3K/AKT/mTOR通路在卵巢癌中的作用
The Role of PI3K/Akt/mTOR Pathway in Ovarian Cancer[J]. 世界肿瘤研究, 2022, 12(03): 199-203. https://doi.org/10.12677/WJCR.2022.123027

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    33. NOTES

    *通讯作者。

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