磷脂酰肌醇-3-激酶/丝苏氨酸蛋白激酶(PI3K/Akt)信号转导通路与子宫颈癌关系的研究现状

磷脂酰肌醇-3-激酶/丝苏氨酸蛋白激酶(phosphateidylinositol 3 kinase/serine-threonine kinase,PI3K/Akt)信号转导通路作为细胞内重要的信号转导通路之一,通过诱导肿瘤细胞的增殖、抗凋亡、促进肿瘤血管的形成及拮抗放化疗等作用在肿瘤的演变过程中起着重要的作用.研究显示,PI3K/Akt信号转导通路与宫颈癌的发生、发展关系密切.本文就PI3K/Akt信号转导通路的结构与功能及其调控机制,在肿瘤发生、发展中的作用以及与子宫颈癌关系的研究进展作一综述.     

PI3K/Akt信号通路及其抑制剂的研究进展

磷脂酰肌醇3激酶（PI3K）/丝氨酸-苏氨酸激酶（Akt）信号通路在信号转导的调控中扮演着重要角色,能调节细胞增殖、凋亡、代谢、运动、血管生成等生物过程。与其他信号通路相比,PI3K/Akt信号通路的组成部分更庞大,在肿瘤中更多见。目前已证实多种肿瘤中存在PI3K/Akt信号通路的超活化,对肿瘤细胞的存活、生长、运动、血管生成和代谢意义重大。因此,抑制PI3K和与通路相关的成分可能会使肿瘤生长受抑,使患者预后改善。PI3K/Akt信号通路抑制剂包括针对单一成分的抑制剂和双重抑制剂。目前大量的PI3K抑制剂已在临床前期研究中取得良好结果,有些已经在血液恶性肿瘤和实体肿瘤中进行了临床试验。在此综述中,我们简单的总结了PI3K-AKt通路的研究成果,讨论了PI3K抑制剂从临床前研究到临床研究的发展前景。     

磷脂酰肌醇3激酶/蛋白激酶B/雷帕霉素靶蛋白信号通路在肺部疾病中的研究进展

磷脂酰肌醇3激酶/蛋白激酶B/雷帕霉素靶蛋白(phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin,PI3K/Akt/mTOR)是细胞内重要信号通路,在细胞生长、增殖、分化和蛋白合成等过程中起重要作用.肺癌、哮喘、肺动脉高压、肺纤维化、慢性阻塞性肺疾病(chronic pulmonary obstructive disease,CORD)等疾病是呼吸系统常见疾病,其病理机制涉及细胞增殖及凋亡等,与PI3K/Akt/mTOR信号通路关系密切.     

PI3K/Akt/mTOR信号通路及其相关基因突变与子宫内膜癌靶向性药物治疗的研究进展

子宫内膜癌(EC)是最常见的女性生殖道恶性肿瘤之一,其发生发展的分子生物学机制十分复杂。近年来研究发现,磷脂酰肌醇-3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白(PI3K/Akt/mTOR)信号通路调节异常与子宫内膜癌密切相关。PI3K/Akt/mTOR信号通路中的多种受体及激酶的突变和异常激活,可能成为子宫内膜癌治疗的靶点。     

PI3K/Akt信号转导通路与胶质母细胞瘤靶向治疗研究进展

胶质母细胞瘤(GBM)是脑部肿瘤中最常见和恶性程度最高的肿瘤。GBM多伴发表皮生长因子受体(EGFR)的过表达或突变。EGFR的异常可导致下游信号转导通路的激活。大量研究显示,磷脂酰肌醇3-激酶(PI3K)信号转导通路是参与GBM发生和恶性演进的重要核心通路之一。本文阐述GBM中PUK/Akt/mTORfq号转导通路的活化过程,分析通过抑制该通路进行GBM靶向治疗的机理,介绍PI3K抑制剂在临床前期研究中的进展,归纳导致疗效降低的原因及可能的解决方案。     

PI3K/Akt信号通路与骨破坏：问题与机制

文题释义：PI3K/Akt信号通路：PI3K/Akt信号通路是由酶联受体介导的能够调节细胞生命活动的信号通路,该通路可以在多种生长因子、细胞因子、细胞外基质等参与下引起信号通路的活化,同时还在细胞增殖、凋亡、组织炎症、肿瘤生长侵袭等方面起着重要作用。近年的研究表明,PI3K/Akt信号通路参与骨质疏松、骨关节炎、骨肉瘤等病理性骨病,并且在破骨细胞和成骨细胞的增殖、分化及凋亡方面扮演着重要角色。 骨破坏：当破骨细胞发挥了骨吸收的功能时,会吸收大量骨质,形成骨吸收陷窝,使骨吸收量大于骨形成量,形成骨质的破坏。 背景：近年来研究表明,PI3K/Akt信号通路与骨破坏相关的疾病密切,并且对靶向该信号通路的抑制剂也在进行大量的研究,这为临床上骨破坏相关疾病的药物治疗提供了新思路。 目的：就PI3K/Akt信号通路在骨破坏中的研究做一综述。 方法：检索1998年1月至2019年8月 PubMed 数据库及万方医学数据库。英文检索词为“PI3K/Akt signaling pathway,osteoclasts,osteoblasts,bone destruction”,中文检索词为“PI3K/Akt信号通路;破骨细胞;成骨细胞;骨破坏”。经过文题、摘要的筛选,排除与研究目的相关性差及内容陈旧、重复的文献,对最终符合标准的67篇文献进行综述。 结果与结论：①成骨细胞和破骨细胞介导的骨形成与骨吸收之间的适当平衡对于维持骨稳态是必要的,这两个生物学过程之间的失衡将导致骨破坏;②PI3K/Akt信号通路是调节细胞生命活动的信号转导通路,在细胞增殖、凋亡、分化等方面起着重要作用;③PI3K/Akt细胞信号通路通过促进成骨细胞增殖、分化和骨形成而参与骨质疏松的抑制;④结果提示,可以研究该信号通路在骨破坏相关疾病中的抑制剂,从而为临床药物治疗提供新思路。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

mTOR信号通路与细胞凋亡

哺乳类动物雷帕霉素靶蛋白(mTOR)主要通过上游信号转导通路磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(PKB/Akt)/mTOR信号通路及下游信号通路mTOR/ eIF4E结合蛋白1(4EBP1)、mTOR/p70S6激酶(p70S6K)在细胞生长、增值与分化和在血管再生、蛋白合成与降解中发挥作用.细胞凋亡是细胞的一种程序性死亡,在机体发育、组织代谢中有着重要作用,而细胞凋亡的异常调节与许多疾病的发生和发展紧密相连.近年研究发现,mTOR信号通路在细胞凋亡过程中扮演了重要角色,并已被作为新的药物治疗靶点.     

雌激素受体ERα与PI3K/Akt细胞信号通路

雌激素直接与核内雌激素受体ERα或ERβ结合,活化靶基因的转录,这是经典的雌激素受体信号转导途径。近年来大量实验证实,雌激素受体ERα能够通过雌激素依赖或不依赖的方式激活,并与细胞质内的磷脂酰肌醇3-激酶-蛋白质丝氨酸苏氨酸激酶(PI3K/Akt)细胞信号传导通路相互作用,发挥重要的生物学效应,如参与人类雌激素相关肿瘤的发病、调节靶细胞的增殖和分化。此外,实验研究还提示,ERα和PI3K/Akt信号通路在哺乳动物植入前胚的发育过程中也起着重要调节作用。     

PI3K/Akt信号通路在乳腺癌内分泌治疗耐药中的作用及对策

乳腺癌是女性最常见的肿瘤,大约75％的乳腺癌表达雌激素受体和/或孕激素受体.激素受体阳性的转移性乳腺癌患者通常采用内分泌治疗,然而由于内分泌治疗耐药的产生,其应用受到了限制.近年来发现,PI3K/Akt(丝氨酸/苏氨酸激酶)信号通路在乳腺癌的发展中发挥着重要作用.本文对PI3K/Akt信号通路在乳腺癌内分泌治疗耐药中的作用进行了综述,以期为雌激素受体阳性乳腺癌治疗提供新对策.     

PI3K / Akt / mTOR 信号通路介导的N822K 突变对c-KIT 抑制剂诱导的AML 细胞凋亡的影响

目的:研究c-KIT N822K 突变对c-KIT 抑制剂诱导AML 细胞凋亡的影响,并初步探讨相关的分子机制。方法:以c-KIT N822K 突变的Kasumi-1 细胞为实验组,以HL-60、NB4 细胞为非c-KIT N822K 突变的对照组,分别用0、0.04、0.16、0.64 μmol/ L 的c-KIT 抑制剂舒尼替尼处理这三株AML 细胞24 h 后收集细胞,采用Western blot 检测凋亡相关蛋白和PI3K/ Akt/ mTOR 通路蛋白水平,比较各组细胞相关信号通路蛋白的变化。结果:随着舒尼替尼浓度的增加,HL-60 及NB4 细胞中Bax 及CytoC、Caspase-9、Actived-Caspase-3、PARP 蛋白剪切体等促凋亡相关蛋白表达均上调(P<0.05),抗凋亡蛋白Bcl-2表达均下调(P<0.01),在具有N822K 突变的Kasumi-1 细胞中这一变化趋势则明显减弱;Kasumi-1 细胞中c-myc 蛋白及PI3K、Akt、4EBP1、mTOR 等PI3K/ Akt/ mTOR 通路蛋白的磷酸化水平均出现剂量依赖性下调(P<0.05),而HL-60 细胞和NB4 细胞则无此变化。结论:N822K 突变引起的c-KIT 结构性激活可影响c-KIT 抑制剂舒尼替尼对Kasumi-1 细胞的凋亡诱导作用,其机制可能与PI3K/ Akt/ mTOR 通路抑制有关。     

Ginkgol C17:1 inhibits tumor growth by blunting the EGF-PI3K/Akt signaling pathway

Ginkgol C17:1 has been shown to inhibit apoptosis and migration of cancer cells, but the underlying mechanisms are not fully elucidated. In this study, we explored whether the inhibitory effects of Ginkgol C17:1 were associated with epidermal growth factor receptor (EGFR) and PI3K/Akt signaling. The results showed that EGF treatment increased the phosphorylation of EGFR, PI3K, Akt, mTOR and NF-kB, and also enhanced the proliferation, migration and invasion of HepG2 cells. Ginkgol C17:1 dose-dependently inhibited EGF-induced phosphorylation/activation of all the key components including EGFR, PI3K, Akt, mTOR and NF-kB, leading to a significant reduction either of proliferation or migration and invasion of HepG2 cells. Notably, treatment with Ginkgol C17:1 in mice suppressed the growth of tumor mass in vivo, and expression of EGFR in the tumor tissue. The results suggest that Ginkgol C17:1 is a potent tumor inhibiting compound that acts on EGF-induced signal transduction of the PI3K/vjjhhAkt signaling pathways, and may represent a clinically interesting candidate for cancer therapy.     

Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder

Sun C‐H, Chang Y‐H & Pan C‐C
(2011) Histopathology 58 , 1054–1063
Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder Aims: Phosphatidylinositol3‐kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway dysregulation has been implicated in the development of urothelial carcinoma. However, its clinical relevance has not been substantially validated in human samples. The aim of this study was to assess the expression of the pathway in a large cohort of bladder cancers using the tissue microarray technique. Methods and results: Immunohistochemical stains for phosphatase and tensin homologue (PTEN), phosphorylated Akt, mTOR, S6 and 4E‐BP1 were performed for 887 cases, and the results were correlated with clinicopathological characteristics. The high expression of p‐S6 and p‐Akt corresponded significantly with high‐grade and advanced‐stage, while losses of PTEN and p‐4E‐BP1 were observed more often in high‐grade and high‐stage tumours. High expression of p‐Akt and p‐S6 predicted progression and cancer‐specific mortality for non‐muscle‐invasive cancers treated by transurethral resection, and p‐Akt was an independent factor in multivariate analysis. High expression of p‐mTOR and p‐Akt correlated with higher cumulative incidence of cancer‐specific mortality for muscle‐invasive cancer, and p‐mTOR was an independent prognostic factor. Conclusions: We have demonstrated the impact of PI3K/Akt/mTOR alteration on the biological behaviour of bladder tumours. Proper immunohistochemical examination of the PI3K/Akt/mTOR pathway can provide useful prognostic information, and the findings may represent an additional therapeutic avenue in the treatment of bladder cancers.     

Targeting the PI3K/Akt/mTOR Pathway in Malignancy: Rationale and Clinical Outlook

The phosphatidylinositol 3-kinase (PI3K) pathway, including major downstream effectors Akt and mammalian target of rapamycin (mTOR), plays a critical role in malignant transformation and subsequent processes of growth, proliferation, and metastases. Not surprisingly, the PI3K/Akt/mTOR pathway has emerged as an attractive drug target and numerous agents directed against various elements of the pathway are currently in clinical development. While early clinical trials with the first generations of these agents have shown limited single-agent efficacy, efforts are now focused on the development of more specific inhibitors, patient selection strategies, and combinational approaches. In this review, we discuss the PI3K/Akt/mTOR pathway in cancer, the rationale for its emergence as a therapeutic target, and progress thus far in the clinical development of inhibitors targeting its various elements.     

Epigallocatechin-3-gallate （EGCG） attenuates nflammation in MRL/Ipr mouse mesangial cells

Epigallocatechin-3-gallate (EGCG), a bioactive component of green tea, has been reported to exert anti-inflammatory effects on immune cells. EGCG is also shown to activate the metabolic regulator, adenosine 5''-monophosphate-activated protein kinase (AMPK). Reports have also indicated that EGCG inhibits the immune-stimulated phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. The PI3K/Akt/mTOR pathway has been implicated in mesangial cell activation in lupus. Mesangial cells from MRL/lpr lupus-like mice are hyper-responsive to immune stimulation and overproduce nitric oxide (NO) and other inflammatory mediators when stimulated. In our current studies, we sought to determine the mechanism by which EGCG attenuates immune-induced expression of pro-inflammatory mediators. Cultured mesangial cells from MRL/lpr mice were pre-treated with various concentrations of EGCG and stimulated with lipopolysaccharide (LPS)/interferon (IFN)-γ. EGCG activated AMPK and blocked LPS/IFN-γ-induced inflammatory mediator production (iNOS expression, supernatant NO and interleukin-6). Interestingly, EGCG attenuated inflammation during AMPK inhibition indicating that the anti-inflammatory effect of EGCG may be partially independent of AMPK activation. Furthermore, we found that EGCG effectively inhibited the immune-stimulated PI3K/Akt/mTOR pathway independently of AMPK, by decreasing phosphorylation of Akt, suggesting an alternate mechanism for EGCG-mediated anti-inflammatory action in mesangial cells. Taken together, these studies show that EGCG attenuated inflammation in MRL/lpr mouse mesangial cells via the PI3K/Akt/mTOR pathway. Our findings suggest a potential therapeutic role for the use of EGCG to regulate inflammation and control autoimmune disease.     

Combined therapeutic application of mTOR inhibitor and vitamin D3 for inflammatory bone destruction of rheumatoid arthritis

Inflammatory bone destruction is a prominent feature and a cause of substantial morbidity in several inflammatory diseases, including rheumatoid arthritis (RA), periodontitis, and peri-prosthetic loosening. Osteoclasts are unique, multinucleated giant cells that effectively resorb bone and thus are directly responsible for bone destruction in several inflammatory diseases. PI3K/Akt/mTOR pathway has been well known to play important roles in regulating adaptive and innate immune cell function. In addition to play roles in immune responses, several lines of evidence demonstrate that PI3K/Akt/mTOR pathway is critical for osteoclast differentiation and survival. These results suggest that inhibition of PI3K/Akt/mTOR pathway could protect against bone destruction in inflammatory diseases, including RA. However, the clinical use of mTOR inhibitors may be hampered due to limited clinical efficacy and frequent toxic side effects. In the treatment of RA, combination therapy with various disease-modifying antirheumatic drugs (DMARDs) has been suggested to improve the therapeutic efficacy and limit the side effects. In this report, we show several experimental evidences that vitamin D₃ modulates mTOR pathway, and present a hypothesis that the combination of mTOR inhibitor and vitamin D₃ can effectively inhibit osteoclast differentiation and function in chronic inflammatory condition such as RA, therefore this combination will be a powerful therapeutic regimen in preventing the inflammation-induced bone destruction in RA.     

The proangiogenic phenotype of human tumor-derived endothelial cells depends on thrombospondin-1 downregulation via phosphatidylinositol 3-kinase/Akt pathway

umor-derived endothelial cells (TEC) display increased survival and angiogenic properties in respect to normal endothelial cells. The aim of this study was to investigate the mechanism potentially involved in TEC proangiogenic phenotype. We found that thrombospondin-1 (TSP-1), a potent physiological inhibitor of angiogenesis, was significantly reduced in TEC in respect to normal endothelial cells. This reduction was confirmed by immunofluorescence in the intratumor vessels of clear cell renal carcinomas. As TEC were shown to display a basal upregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, we evaluated the possible regulation of TSP-1 by this pathway by using LY294002 and wortmannin, the PI3K inhibitors, and rapamycin, the mammalian target of rapamycin (mTOR) inhibitor. In addition, we developed negative dominant TEC for Akt. TSP-1 production by TEC was enhanced by the treatment with LY294002 and wortmannin and with rapamycin, suggesting a negative regulation of TSP-1 expression by the PI3K/Akt/mTOR pathway. In addition, downregulation of Akt activation in negative dominant Akt TEC enhanced TSP-1 expression and release. Administration of exogenous TSP-1 to TEC reduced their proangiogenic properties in vitro and in vivo. In parallel, blockade of TSP-1 with an anti-TSP-1 antibody in negative dominant Akt TEC restored their proangiogenic phenotype to levels similar to wild-type TEC. In conclusion, these results indicate that the upregulation of the PI3K/Akt/mTOR pathway is responsible for the inhibition of TSP-1 synthesis which is critical in determining the proangiogenic phenotype of TEC. Strategies aimed to inhibit the PI3K/Akt/mTOR pathway may restore a normal quiescent endothelial phenotype in TEC by promoting TSP-1 production.