PI3K/Akt/mTOR信号传导通路与恶性肿瘤浸润和转移的研究进展

PI3K/Akt/mTOR信号通路作为细胞内重要信号传导通路之一,通过影响下游多种效应分子的活化状态,在细胞内发挥着抑制凋亡、促进增殖的关键作用,它与人类多种肿瘤的发生发展密切相关.本文综述了PI3K/Akt/mTOR信号通路的组成与功能、调节以及其抗肿瘤细胞凋亡作用机理等方面的研究进展,并就其抗细胞凋亡作用在肿瘤治疗中的应用作了评述,期待为以PI3K/Akt/mTOR信号通路中关键分子为靶点的肿瘤治疗研究提供参考.     

mTOR功能及其抑制剂研究进展

哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin mTOR）是一种丝／苏氨酸蛋白激酶，mTOR在肿瘤细胞生长、增殖过程中起重要作用，mTOR信号通路活动异常与肿瘤的发生有密切关系，mTOR足肿瘤药物治疗作用的理想靶点，目前新的mTOR抑制剂不断出现。本文对mTOR蛋白的结构、功能和mTOR信号通路及其抑制剂进行了综述。     

PI3K／Akt／inTOR信号传导通路与恶性肿瘤浸润和转移的研究进展

PI3K／Akt／mTOR信号通路作为细胞内重要信号传导通路之一,通过影响下游多种效应分子的活化状态,在细胞内发挥着抑制凋亡、促进增殖的关键作用,它与人类多种肿瘤的发生发展密切相关。本文综述了PI3K／Akt／mTOR信号通路的组成与功能、调节以及其抗肿瘤细胞凋亡作用机理等方面的研究进展,并就其抗细胞凋亡作用在肿瘤治疗中的应用作了评述,期待为以PI3K／Akt／mTOR信号通路中关键分子为靶点的肿瘤治疗研究提供参考。     

P53蛋白介导mTOR信号途径影响肿瘤细胞自噬的研究进展

自噬是机体内的一种代谢方式,参与调控多种生理病理过程,受不同信号级联反应调节,在维持细胞生长与代谢等方面起关键作用。哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin,mTOR）是一种蛋白激酶,也是调节细胞生长和增殖的重要信号分子,其通路的异常激活与肿瘤的发生发展密切相关且可通过调节细胞自噬治疗肿瘤。 p53 为抑癌基因,具有抑制癌症形成的作用。近来研究显示,胞质和胞核中均存在P53蛋白,在核内P53可通过活化腺苷酸活化的蛋白激酶（adenosine monophosphate activated protein kinase,AMPK）激活抑癌基因与张力蛋白同源10q丢失的磷酸酶基因（phosphatase and tensin homolog deleted on chromosome ten,PTEN）的转录等机制来调节mTOR信号通路相关分子,抑制mTOR活性,促使UNC-51激酶1（unc-51-like kinase1,ULK1）去磷酸化而增强自噬,亦可介导某些凋亡蛋白（Bcl-2、Bax等）及调控因子（DRAM、PUMA等）的信号通路参与自噬调节,但与mTOR通路的关系尚待研究;细胞质中的P53蛋白以非依赖转录的方式如降解P53、抑制RB1CC1/FIP200活性等,参与mTOR途径调控,抑制自噬。本文就P53蛋白介导mTOR信号途径影响肿瘤细胞自噬的研究进展作一综述。     

哺乳动物雷帕霉素靶蛋白及其信号通路在胃癌中的研究进展

哺乳动物雷帕霉素靶蛋白(mTOR)及其信号通路控制着蛋白质合成、细胞的生长和代谢以及血管的生成等.其信号通路在胃癌中常被高度激活,与胃癌进展及预后密切相关.雷帕霉素及其衍生物可通过阻断mTOR通路的信号传递,抑制胃癌细胞生长,促进肿瘤坏死,并能与其他化疗药物产生协同作用,有望为胃癌预防和治疗提供有效的方法.     

哺乳动物雷帕霉素靶蛋白及其信号通路在胃癌中的研究进展

哺乳动物雷帕霉素靶蛋白(mTOR)及其信号通路控制着蛋白质合成、细胞的生长和代谢以及血管的生成等.其信号通路在胃癌中常被高度激活,与胃癌进展及预后密切相关.雷帕霉素及其衍生物可通过阻断mTOR通路的信号传递,抑制胃癌细胞生长,促进肿瘤坏死,并能与其他化疗药物产生协同作用,有望为胃癌预防和治疗提供有效的方法.     

PI3K/Akt/mTOR信号通路抑制剂在乳腺癌中的研究进展

目的:总结PI3K/Akt/mTOR信号通路靶向治疗在乳腺癌中的研究进展.方法:以“PI3K/Akt/mTOR、信号通路和乳腺癌”等为关键词,检索2000-01-2011-06 PubMed、Ovid和Springer等数据库的相关文献.纳入标准:1)关于PI3K/Akt/mTOR信号通路的组成、功能特点;2)PI3K/Akt/mTOR信号通路与乳腺癌的关系研究;3)以PI3K/Akt/mTOR信号通路中关键分子为靶点的乳腺癌治疗.根据纳入标准,符合分析的文献40篇.结果:信号转导通路的异常是肿瘤发生、发展的重要步骤,PI3K/Akt/mTOR信号通路与人类多种肿瘤密切相关,其在肿瘤细胞的增殖、存活、抵抗凋亡、血管发生和转移以及对放化疗抵抗中发挥了重要作用.乳腺癌中常见PI3K/Akt/mTOR信号通路的异常激活,以此通路为靶点的药物已成为乳腺癌治疗的研究热点.结论:靶向PI3K/Akt/mTOR通路中关键分子的众多药物在乳腺癌开展了一系列相关的临床试验研究,一部分显示出较好的安全性和有效性.随着对PI3K/Akt/mTOR通路的分子生物学机制的深入研究,期待靶向此通路的抑制剂将会在乳腺癌治疗中发挥巨大的作用,进一步提高乳腺癌患者的疗效和改善预后.     

mTOR信号通路调控CD133阳性胶质瘤干细胞自我更新的分子机制

背景与目的：mTOR（mammalian target of rapamycin）信号通路异常活化和高级别胶质瘤患者的预后不良相关。本研究探讨mTOR信号通路调控胶质瘤干细胞（GSCs）自我更新相关的分子机制。方法：采用CD133免疫磁珠分选CD133阳性胶质瘤干细胞。Western blot检测mTOR信号通路组分p-S6K、p-S6和干细胞自我更新相关基因Bmi-1的表达水平;Rapamycin（RPA）阻断mTOR信号通路后,用肿瘤球形成实验评价干预mTOR信号通路对胶质瘤干细胞自我更新的影响;统计学处理采用SPSS11.0统计分析软件分析。结果：CD133阳性胶质瘤干细胞表达较高水平的mTOR信号通路组分p-S6K、p-S6和干细胞自我更新相关分子Bmi-1。通过rapamycin阻断mTOR信号通路,可诱导胶质瘤干细胞谱系分化,同时显著降低肿瘤球形成能力（P〈0.05）,而自噬抑制剂3-MA处理不能逆转rapamycin的效应。结论：mTOR信号通路能够调控胶质瘤干细胞自我更新,阻断mTOR通路下调胶质瘤干细胞自我更新潜能。     

哺乳动物雷帕霉素靶蛋白信号通路与大肠癌

哺乳动物雷帕霉素靶蛋白(mTOR)信号通路作为细胞内重要信号转导通路之一,通过影响下游多种效应分子的活化状态,调节细胞存活、增殖、转分化、迁移和细胞周期.mTOR这些调节机制的异常与大肠癌的发生和发展密切相关.目前mTOR抑制剂治疗大肠癌已处于临床试验中,并取得了一定的进展.     

MAG - 1 和 mTOR 生物学功能研究进展

PI3K/Akt/mTOR信号传导通路是细胞内重要的信号传导通路之一,mTOR是该通路的焦点,其上游和下游效应分子的不同活化状态对细胞的增殖、运动等生物学功能发挥重要作用.MAG-1是近年来新发现的mTOR上游效应分子,通过mTOR信号传导通路发挥生物学功能.本文就MAG-1和mTOR生物学功能研究进展作一综述.     

Targeting the mTOR-DEPTOR Pathway by CRL E3 Ubiquitin Ligases: Therapeutic Application

The mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine protein kinase, integrates both intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation, survival, and autophagy. The mTOR pathway is frequently activated in many human cancers, mainly resulting from alterations in the upstream regulators, such as phosphoinositide 3-kinase (PI3K)/AKT activation, PTEN loss or dysregulation of mTOR-negative regulators (e.g., TSC1/2), leading to uncontrolled proliferation. Thus, inhibiting the PI3K/AKT/mTOR pathways is widely considered as an effective approach for targeted cancer therapy. Recently, we and others found that DEPTOR, a naturally occurring inhibitor of both mTORC1 and mTORC2, was degraded by SCF (Skp1-Cullin-F box proteins) E3 ubiquitin ligase, the founding member of cullin-RING-ligases (CRLs), resulting in mTOR activation and cell proliferation. In addition to DEPTOR, previous studies have demonstrated that several other negative regulators of mTOR pathway are also substrates of CRL/SCF E3s. Thus, targeting CRL/SCF E3s is expected to cause the accumulation of these mTOR signal inhibitors to effectively block the mTOR pathway. In this review, we will discuss mTOR signaling pathway, how DEPTOR regulates mTOR/AKT axis, thus acting as a tumor suppressor or oncogene in some cases, how DEPTOR is ubiquitinated and degraded by SCF^β-TrCP E3, and how MLN4924, a small-molecule indirect inhibitor of CRL/SCF E3 ligases through blocking cullin neddylation, might be useful as a novel approach of mTOR pathway targeting for cancer therapy.     

PI3K/AKT/mTOR pathway activation in primary and corresponding metastatic breast tumors after adjuvant endocrine therapy

Both preclinical and clinical data suggest that activation of the PI3K/AKT/mTOR pathway in response to hormonal therapy results in acquired endocrine therapy resistance. We evaluated differences in activation of the PI3K/AKT/mTOR pathway in estrogen receptor α (ERα) positive primary and corresponding metastatic breast cancer tissues using immunohistochemistry for downstream activated proteins, like phosphorylated mTOR (p‐mTOR), phosphorylated 4E Binding Protein 1 (p‐4EBP1) and phosphorylated p70S6K (p‐p70S6K). For p‐mTOR and p‐4EBP1, the proportion of immunostained tumor cells (0–100%) was scored. Cytoplasmic intensity (0–3) was assessed for p‐p70S6K. The difference between expression of these activated PI3K/AKT/mTOR proteins‐ in primary and metastatic tumor was calculated and tested for an association with adjuvant endocrine therapy. In patients who had received endocrine therapy (N = 34), p‐mTOR expression increased in metastatic tumor lesions compared to the primary tumor (median difference 45%), while in patients who had not received adjuvant endocrine therapy (N = 37), no difference was found. Similar results were observed for p‐4EBP1 and p‐p70S6K expression. In multivariate analyses, adjuvant endocrine therapy was significantly associated with an increase in p‐mTOR (p = 0.01), p‐4EBP1 (p = 0.03) and p‐p70S6K (p = 0.001), indicating that compensatory activation of the PI3K/AKT/mTOR pathway might indeed be a clinically relevant resistance mechanism resulting in acquired endocrine therapy resistance.     

哺乳动物雷帕霉素靶蛋白的反馈激活机制在肿瘤中的研究进展

哺乳动物雷帕霉素靶蛋白（mTOR）作为生长因子和氨基酸特别是亮氨酸所激发的信号通路的汇合点,在肿瘤细胞中起中心调控作用.近些年,人们逐渐认识到mTOR的反馈激活机制是影响雷帕霉素及其类似物抗肿瘤疗效的重要因素之一.因此,针对mTOR的反馈激活机制及联合应用相关抑制剂协同阻断这一机制的研究成为肿瘤防治的新热点.     

Phosphoprotein pathway mapping: Akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival

Mapping of protein signaling networks within tumors can identify new targets for therapy and provide a means to stratify patients for individualized therapy. Despite advances in combination chemotherapy, the overall survival for childhood rhabdomyosarcoma remains approximately 60%. A critical goal is to identify functionally important protein signaling defects associated with treatment failure for the 40% nonresponder cohort. Here, we show, by phosphoproteomic network analysis of microdissected tumor cells, that interlinked components of the Akt/mammalian target of rapamycin (mTOR) pathway exhibited increased levels of phosphorylation for tumors of patients with short-term survival. Specimens (n = 59) were obtained from the Children's Oncology Group Intergroup Rhabdomyosarcoma Study (IRS) IV, D9502 and D9803, with 12-year follow-up. High phosphorylation levels were associated with poor overall and poor disease-free survival: Akt Ser(473) (overall survival P < 0.001, recurrence-free survival P < 0.0009), 4EBP1 Thr(37/46) (overall survival P < 0.0110, recurrence-free survival P < 0.0106), eIF4G Ser(1108) (overall survival P < 0.0017, recurrence-free survival P < 0.0072), and p70S6 Thr(389) (overall survival P < 0.0085, recurrence-free survival P < 0.0296). Moreover, the findings support an altered interrelationship between the insulin receptor substrate (IRS-1) and Akt/mTOR pathway proteins (P < 0.0027) for tumors from patients with poor survival. The functional significance of this pathway was tested using CCI-779 in a mouse xenograft model. CCI-779 suppressed phosphorylation of mTOR downstream proteins and greatly reduced the growth of two different rhabdomyosarcoma (RD embryonal P = 0.00008; Rh30 alveolar P = 0.0002) cell lines compared with controls. These results suggest that phosphoprotein mapping of the Akt/mTOR pathway should be studied further as a means to select patients to receive mTOR/IRS pathway inhibitors before administration of chemotherapy.     

mTOR的反馈激活机制及其抑制剂的抗肿瘤应用

mTOR是处于调节细胞代谢、生长、增殖等整个过程中心环节的重要激酶。干扰或抑制mTOR会引起细胞尤其是癌细胞的生长停滞继而死亡,因而也被公认为是癌症治疗当中的一个潜在靶标。一系列的mTOR抑制剂Rapamycin及类似物已经形成并在临床抗肿瘤中有所应用,但其展示的效应非常有限。随着研究的深入,发现mTOR信号通路存在反馈激活机制:即抑制mTOR能反馈性激活多个与细胞生长增殖相关的信号通路。并且认为是这些反馈激活机制削弱了mTOR抑制剂的效能,也是其临床效应未达预期的原因。本文就目前国内外研究较深入的mTOR-AKT,mTOR-ERK,mTOR-eIF4E反馈信号通路做详细概述,并阐述目前采取的防止这一反馈机制形成的Rapamycin类似物与特定通路抑制剂的联合用药策略,使mTOR抑制剂在临床抗肿瘤中能充分发挥其效能。      

mTOR抑制剂在激素受体阳性乳腺癌治疗中的研究进展

靶向激素受体（hormone receptor,HR）和人类表皮生长因子（human epidermal growth factor receptor 2,HER-2）对激素受体阳性乳腺癌的治疗至关重要,然而原发或继发内分泌治疗耐药及后续的疾病进展仍不可避免。人哺乳动物雷帕霉素位点（mammalian target of rapamycin,mTOR）是细胞生长和分化的关键调节因子,参与细胞不可控性生长。目前许多研究表明mTOR通路的激活可能与乳腺癌内分泌治疗耐药相关,阻断此通路有助于消除耐药,维持药物的敏感性。许多靶向mTOR通路的药物均表现出强大的抗肿瘤效应,在乳腺癌治疗中具有良好前景,且已有许多临床试验结果表明mTOR抑制剂联合内分泌治疗可显著提高患者的生存率。本文对mTOR信号通路及其抑制剂在内分泌治疗耐药的乳腺癌中的新进展进行综述。      

mTOR抑制剂在乳腺癌内分泌治疗耐药中的研究进展

PI3K/Akt/mTOR信号转导通路可抑制肿瘤细胞凋亡、促进细胞生存、调节细胞周期,促进肿瘤新生血管的形成以及侵袭与转移,在肿瘤的发生、发展、治疗及转归中发挥着重要作用。该信号通路与乳腺癌关系非常密切,是乳腺癌新的治疗靶点及研究热点。mTOR抑制剂通过不同的靶点作用于PI3K/Akt/mTOR信号转导通路上,从而达到其抗癌作用。内分泌治疗是乳腺癌的重要治疗方式之一,与化疗等其他治疗方式一样,内分泌治疗同样也面临治疗耐受这一难题。随着越来越多的信号通路被揭示,单一阻断某一位点已经不能满足治疗的需要,寻找多条通路的共同抑制位点成为研究人员关注的焦点。本文就mTOR抑制剂在乳腺癌内分泌治疗耐药中的作用及其临床试验结果进行综述,以期进一步了解mTOR抑制剂的临床作用。      

Combination of PI3K/mTOR inhibitors: antitumor activity and molecular correlates

The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway is a major target for cancer therapy. As a strategy to induce the maximal inhibition of this pathway in cancer cells, we combined allosteric mTOR inhibitors (rapamycin and RAD001) with a dual PI3K/mTOR kinase inhibitor (PI-103). Both in vitro and in vivo, the combination exhibited more activity than single agents in human ovarian and prostate cancer cells that harbor alterations in the pathway. At the molecular level, combined inhibition of mTOR prevented the rebound activation of Akt that is seen after treatment with rapamycin and its analogues and caused more sustained inhibition of Akt phosphorylation. Furthermore, the combination strongly inhibited the expression of PI3K/Akt/mTOR downstream proteins. In particular, it showed greater activity than the single agents in inhibiting the phosphorylation of 4EBP1, both in vitro and in vivo, resulting in selective inhibition of CAP-dependent translation. A proteomic approach was used to confirm the identification of c-Myc as the key regulator for the reduction in downstream proteins affected by the combined inhibition of mTOR. In conclusion, the combination of a catalytic and an allosteric inhibitor of mTOR shows greater activity, without a concomitant increase in toxicity, than either drug alone, and this may have therapeutic implications for inhibiting this pathway in the clinical setting.     

The dual PI3K and mTOR inhibitor NVP-BEZ235 exhibits anti-proliferative activity and overcomes bortezomib resistance in mantle cell lymphoma cells

Mantle cell lymphoma (MCL) is one of the most difficult B-cell lymphomas to be treated. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is constitutively activated in MCL and plays a critical role in tumor growth and survival. However, single targeted agent mTOR has limited efficacy in treating MCL. Here, we investigate for the first time potential efficacy of NVP-BEZ235 (BEZ235) in treating MCL by simultaneously targeting Akt and mTOR. In this study, phosphorylated Akt and mTOR level were elevated in tissue samples from MCL patients and in MCL cell lines. We also generated bortezomib-resistant MCL cell lines and found increased phosphorylation of Akt and mTOR. Individual inhibition of PI3K or mTOR had limited anti-proliferative effects, whereas dual inhibition with BEZ235 effectively inhibited cell growth. The effect of BEZ235 was synergistic and sensitized the cells to the cytotoxic effects of conventional agents. Furthermore, BEZ235 could overcome acquired resistance to bortezomib in MCL cells and suppress the activated Akt/mTOR pathway. Therefore, these data suggest that the Akt/mTOR pathway plays a key role in the growth and survival of MCL cells and that these proteins may need to be simultaneously targeted for effective treatment of the disease. Our findings suggest that BEZ235 may be an effective agent for the treatment of MCL.