弥漫大B细胞性淋巴瘤中mTOR信号通路的激活

0引言 mTOR(mallmalian target of rapamycin)属于丝/苏氨酸激酶家族,在细胞生长和增殖控制中发挥着关键作用.在上游,生长信号激活的Akt激酶诱导其磷酸化而活化.下游其磷酸化核糖体蛋白S6激酶(S6 kinase,S6K1,p70S6K)而刺激蛋白质翻译和核糖体形成[1-2].近年来研究表明,多种恶性肿瘤中存在mTOR信号通路的激活[1-2],该通路因此被视为癌症靶向治疗的新的潜在靶点.雷帕霉素作为免疫抑制剂首先应用于预防器官移植排异反应的研究,但随后发现其能通过调节mTOR激酶活性,抑制信号通路的激活而对抗细胞的增殖,因此被视为一种潜在的抗肿瘤药物,临床上,其衍生物CCI-779(Temsirolmus)已被批准用于晚期肾细胞癌的治疗.     

Ghrelin促进乳腺癌细胞MDA-MB-231增殖的分子机制

目的:探讨生长激素释放肽（Ghrelin）促进乳腺癌细胞MDA-MB-231增殖的分子机制。方法:乳腺癌细胞MDA-MB-231经Ghrelin、Ghrelin受体（growth hormone secretagogue receptor,GHSR)抑制剂［D-Lys3］-GHRP-6或哺乳动物雷帕霉素靶蛋白(mammalian target of Rapamycin,mTOR)抑制剂雷帕霉素（Rapamycin）处理后,MTT或BrdU实验检测MDA-MB-231细胞的增殖能力;Western blot检测MDA-MB-231细胞GHSR表达及mTOR、p70S6K和S6磷酸化水平。结果:增殖实验结果表明Ghrelin增强MDA-MB-231细胞增殖能力;Western blot检测发现Ghrelin激活MDA-MB-231细胞mTOR、p70S6K和S6磷酸化,［D-Lys3］-GHRP-6或Rapamycin消除Ghrelin促进MDA-MB-231细胞增殖效应,同时抑制Ghrelin诱导的mTOR、p70S6K和S6磷酸化。结论:Ghrelin通过与GHSR结合激活MDA-MB-231细胞mTOR/p70S6K/S6信号途径促进MDA-MB-231细胞增殖。     

雷帕霉素耐药机制及其逆转途径

雷帕霉素靶蛋白(mTOR)信号通路与肿瘤细胞的增殖、周期调控等多种病理过程密切相关.雷帕霉素通过抑制mTOR起到抗肿瘤作用,但其容易产生耐药等缺点导致临床应用受限,耐药机制主要与mTOR受抑后负反馈激活磷脂酰肌醇3-激酶-蛋白激酶B(PI3K-Akt)有关.mTOR通路相关蛋白的双重抑制剂等药物有望逆转其耐药.     

mTOR通路及其抑制剂抗肿瘤的研究进展

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是PI3K/Akt通路的下游分子,可接受生长因子、营养、能量等多种信号,是细胞生长和增殖的关键调节分子.许多肿瘤中存在有编码mTOR信号通路相关蛋白的基因突变,这些蛋白的异常表达可引起mTOR通路的过度激活.目前,以mTOR为治疗靶点成为肿瘤治疗的研究新热点.本文就近年来有关mTOR通路及其抑制剂在抗肿瘤方面的研究进展作一综述.     

联合靶向mTOR和Gli1/2信号通路的药物对肾癌细胞生长的抑制效应

目的:探讨联合靶向mTOR和Gli1/2信号通路的药物对肾癌细胞生长的抑制效应。方法:采用Real time-PCR的方法检测SHH/Gli信号通路的核心效应成分Gli1和Gli2在20对正常肾脏和肾癌组织中的表达情况;采用Western blot技术验证4对正常肾脏和配对的肿瘤中Gli1和Gli2蛋白的表达水平。单独或联合使用不同浓度的mTOR抑制剂与Gli1/2抑制剂于肾癌细胞后,采用MTT的方法检测细胞的体外增殖能力,然后采用Western blot技术检测联合应用低剂量mTOR抑制剂与Gli1/2抑制剂的肾癌细胞内细胞周期、凋亡相关蛋白的变化情况。结果:Gli1与Gli2在肾癌组织中的表达高于对照的正常肾脏组织。低剂量（5 μmol/L）Gli1/2抑制剂Gant61并不能显著抑制肾癌细胞的生长,高剂量（10 μmol/L）的Gant61能达到有效的抑制效应;但5 μmol/L Gant61与低剂量mTOR抑制剂Rapamycin联用时,肾癌细胞的生长显著被抑制,且诱导细胞凋亡,阻滞细胞周期。结论:联合靶向mTOR和Gli1/2信号通路显著抑制肾癌细胞生长,为潜在的治疗策略。     

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。      

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.     

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.     

PDK／Akt通路与肿瘤治疗

磷酸肌醇-3激酶／蛋白激酶B（phosphoinositide 3-kinase／protein kinaseB，P13K／Akt）信号通路参与很多重要生物学过程的调控，但其过度激活可导致肿瘤的发生。在正常组织中P13K／Akt信号转导途径处于活化状态，但是该通路如果被过度激活则可通过下调肿瘤抑制蛋白p53、刺激蛋白质合成、抑制细胞凋亡等导致肿瘤细胞的无限增殖，成为肿瘤预后不好的标志，因此抑制该通路的激活有利于肿瘤治疗。目前已发现肿瘤抑制基因PTEN、PHLPP和蛋白磷酸酶2A等均可通过不同的机制抑制该通路的激活。同时，针对该通路的抑制剂作为抗肿瘤药物得到了广泛研究并在临床上取得了预期的进展，如wtPTEN的转基因研究、P13K抑制剂LY294002和渥曼青霉素、PDK-1抑制剂星孢菌素和塞来昔布、Akt抑制剂哌立福新、雷帕霉素靶蛋白（mTOR）抑制剂西罗莫司等，期望这些抑制剂能达到靶向治疗肿瘤的目的。     

蛇毒抗肿瘤应用及其机制的研究进展

蛇毒对多种恶性肿瘤细胞有抑制增殖、诱导细胞凋亡和(或)抑制细胞迁移等作用,且呈剂量效应和(或)时间效应关系;此外,蛇毒还具有抗肿瘤血管生成作用。蛇毒抗肿瘤机制如下:1)通过阻断某些信号通路抑制肿瘤转移;2)通过激活死亡信号通路诱导肿瘤细胞凋亡;3)通过调节抑(促)癌基因表达或阻滞细胞周期抑制肿瘤细胞生长和增殖;4)通过抑制肿瘤细胞表达血管内皮生长因子(vascular endothelial growth factor,VEGF)而抑制肿瘤血管生成。蛇毒在抗肿瘤应用方面具有较大的发展空间。本文对近年来国内外蛇毒抗肿瘤应用相关文献资料进行整理和归纳,总结了蛇毒抗肿瘤作用及其机制,以期为蛇毒抗肿瘤成分的研究、开发和应用提供参考。      

Overcoming mTOR inhibition-induced paradoxical activation of survival signaling pathways enhances mTOR inhibitors' anticancer efficacy

The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Several mTOR inhibitors are currently being tested in cancer clinical trials. Both PI3K/Akt and MEK/ERK signaling regulate mTOR axis. However, inhibition of mTOR activates Akt survival signaling, which in turn attenuates mTOR inhibitors' anticancer efficacy. We are interested in developing strategies for enhancing mTOR-targeted cancer therapy. In this study, we report that mTOR inhibition also induced activations of the MEK/ERK signaling pathway in some cancer cell lines after a prolonged treatment. The combination of rapamycin with the MEK inhibitor U0126 significantly enhanced growth inhibitory effects of cancer cells, suggesting that MEK/ERK activation may counteract mTOR inhibitors' anticancer efficacy. Similarly, the combination of an mTOR inhibitor with the EGF receptor inhibitor erlotinib synergistically inhibited the growth of both human cancer cells in cell cultures and xenografts in nude mice. Moreover, the presence of erlotinib suppressed rapamycin-induced phosphorylation of Akt, ERK and eIF4E as well, implying that erlotinib can suppress mTOR inhibition-induced feedback activation of several survival signaling pathways including Akt, ERK and eIF4E. Thus, we suggest a therapeutic strategy for enhancing mTOR-targeted cancer therapy by preventing mTOR inhibition-induced feedback activation of several survival mechanisms.     

PI3K and mTOR Signaling Pathways in Cancer: New Data on Targeted Therapies

The mammalian target of rapamycin (mTOR) and the phosphoinositide 3-kinase (PI3K) signaling pathways are commonly deregulated in cancers and promote cellular growth, proliferation, and survival. mTOR is part of two complexes, mTORC1 and mTORC2, with different biochemical structures and substrates specificity. PI3K/AKT activation may result from genetic hits affecting different components of the pathway, whereas the mechanisms leading to constitutive mTORC1 activation remain globally unknown. The connections between the PI3K and mTOR kinases are multiple and complex, including common substrates, negative feedback loops, or direct activation mechanisms. First-generation allosteric mTOR inhibitors (eg, rapamycin) are mainly active on mTORC1 and mostly display cytostatic anti-tumor activity. Recently, second-generation catalytic mTOR inhibitors targeting both mTOR complexes 1 and 2 have been developed. Some of them also inhibit class IA PI3K. Here, we highlight recent data generated with these new inhibitors against cancer cells and their potential as anti-cancer drugs.     

Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) network plays a key regulatory function in cell survival, proliferation, migration, metabolism, angiogenesis, and apoptosis. Genetic aberrations found at different levels, either with activation of oncogenes or inactivation of tumor suppressors, make this pathway one of the most commonly disrupted in human breast cancer. The PI3K-dependent phosphorylation and activation of the serine/threonine kinase AKT is a key activator of cell survival mechanisms. The activation of the oncogene PIK3CA and the loss of regulators of AKT including the tumor suppressor gene PTEN are mutations commonly found in breast tumors. AKT relieves the negative regulation of mTOR to activate protein synthesis and cell proliferation through S6K and 4EBP1. The common activation of the PI3K pathway in breast cancer has led to the development of compounds targeting the effector mechanisms of the pathway including selective and pan-PI3K/pan-AKT inhibitors, rapamycin analogs for mTOR inhibition, and TOR-catalytic subunit inhibitors. The influences of other oncogenic pathways such as Ras-Raf-Mek on the PI3K pathway and the known feedback mechanisms of activation have prompted the use of compounds with broader effect at multiple levels and rational combination strategies to obtain a more potent antitumor activity and possibly a meaningful clinical effect. Here, we review the biology of the network, its role in the development and progression of breast cancer, and the evaluation of targeted therapies in clinical trials.     

Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer

The phosphoinositide-3 kinase (PI3K) pathway has been identified as an important target in breast cancer research for a number of years, but is new to most clinicians responsible for the daily challenges of breast cancer management. In fact, the PI3K pathway is probably one of the most important pathways in cancer metabolism and growth. Mutations in the PI3K pathway are frequent in breast cancer, causing resistance to human epidermal growth factor receptor 2-targeted agents and, possibly, to hormonal agents as well. Available agents that affect the PI3K pathway include monoclonal antibodies and tyrosine kinase inhibitors, as well as PI3K inhibitors, Akt inhibitors, rapamycin analogs, and mammalian target of rapamycin (mTOR) catalytic inhibitors. Multiple PI3K inhibitors are currently under development, including pure PI3K inhibitors, compounds that block both PI3K and mTOR (dual inhibitors), pure catalytic mTOR inhibitors, and inhibitors that block Akt. It is likely that these agents will have to be given in combination with other signal inhibitors because anti-mTOR agents and PI3K inhibitors may result in the activation of compensatory feedback loops that would in turn result in decreased efficacy. This article reviews current data related to the PI3K pathway, its role in breast cancer, the frequency with which PI3K is aberrant in breast cancer, and the potential clinical implications of using agents that target the PI3K pathway.     

The biology behind mTOR inhibition in sarcoma

Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been found in many human tumors and implicated in the promotion of cancer cell growth and survival. Hence, the mTOR pathway is considered an important target for anticancer drug development. Currently, the mTOR inhibitor rapamycin and its derivatives CCI-779, RAD001, and AP23573 are being evaluated in cancer clinical trials. To date, clinical results have shown good tolerability of treatment with mTOR inhibitors in most reports and varying effectiveness of mTOR inhibitors in a variety of tumors in a subset of patients. For the targeted treatment of sarcomas, AP23573 has shown promising clinical efficacy and low toxicity profiles in patients. Further studies should define the optimal dose/schedule, patient selection, and combination strategies with other biological agents, especially those targeting signaling pathways crucial for cell survival. Disclosure of potential conflicts of interest is found at the end of this article.     

Mammalian target of rapamycin: a new molecular target for breast cancer

The mammalian target of rapamycin (mTOR), a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway that mediates cell survival and proliferation, is a prime strategic target for anticancer therapeutic development. By targeting mTOR, the immunosuppressant and antiproliferative agent rapamycin inhibits signals required for cell cycle progression, cell growth, and proliferation. Both rapamycin and novel rapamycin analogues with more favorable pharmaceutical properties, such as CCI-779, RAD 001, and AP23573, are highly specific inhibitors of mTOR. In essence, these agents gain function by binding to the immunophilin FK506 binding protein 12 and the resultant complex inhibits the activity of mTOR. Because mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1, rapamycin-like compounds block the actions of these downstream signaling elements, which results in cell cycle arrest in the G1 phase. Rapamycin and its analogues also prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which potentially contribute to the prominent inhibitory effects of rapamycin at the G1/S boundary of the cell cycle. Rapamycin and rapamycin analogues have demonstrated impressive growth-inhibitory effects against a broad range of human cancers, including breast cancer, in preclinical and early clinical evaluations. In breast cancer cells, PI3K/Akt and mTOR pathways seem to be critical for the proliferative responses mediated by the epidermal growth factor receptor, the insulin growth factor receptor, and the estrogen receptor. Furthermore, these pathways may be constitutively activated in cancers with many types of aberrations, including those with loss of PTEN suppressor gene function. Therefore, the development of inhibitors of mTOR and related pathways is a rational therapeutic strategy for breast and other malignancies that possess a wide range of aberrant molecular constituents. This review will summarize the principal mechanisms of action of rapamycin and rapamycin derivatives, as well as the potential utility of these agents as anticancer therapeutic agents with an emphasis on breast cancer. The preliminary results of early clinical evaluations with rapamycin analogues and the unique developmental challenges that lie ahead will also be discussed.     

Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: An emerging treatment strategy for squamous cell lung carcinoma

Squamous cell lung carcinoma accounts for approximately 30% of all non-small cell lung cancers (NSCLCs). Despite progress in the understanding of the biology of cancer, cytotoxic chemotherapy remains the standard of care for patients with squamous cell lung carcinoma, but the prognosis is generally poor. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one of the most commonly activated signaling pathways in cancer, leading to cell proliferation, survival, and differentiation. It has therefore become a major focus of clinical research. Various alterations in the PI3K/AKT/mTOR pathway have been identified in squamous cell lung carcinoma and a number of agents targeting these alterations are in clinical development for use as single agents and in combination with other targeted and conventional treatments. These include pan-PI3K inhibitors, isoform-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR inhibitors. These agents have demonstrated antitumor activity in preclinical models of NSCLC and preliminary clinical evidence is also available for some agents. This review will discuss the role of the PI3K/AKT/mTOR pathway in cancer and how the discovery of genetic alterations in this pathway in patients with squamous cell lung carcinoma can inform the development of targeted therapies for this disease. An overview of ongoing clinical trials investigating PI3K/AKT/mTOR pathway inhibitors in squamous cell lung carcinoma will also be included.     

Mammalian target of rapamycin inhibitors in renal cell carcinoma: current status and future applications

Significant achievements in the basic sciences have led to a greater knowledge of the underlying signaling pathways in renal cell cancer (RCC), including the mammalian target of rapamycin (mTOR) pathway (phosphoinositide 3-kinase/Akt pathway). The mTOR pathway has a central role in the regulation of cell growth and increasing evidence suggests its dysregulation in cancer. Receiving input from multiple signals, including growth factors, hormones, nutrients, and other stimulants or mitogens, the pathway stimulates protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase. The mTOR pathway also contributes to many other critical cellular functions, including protein degradation and angiogenesis. Hence, use of inhibitors of the pathway represents a new strategy for the targeted treatment of RCC, and mTOR inhibitors have already shown promising clinical efficacy and low toxicity profiles in unselected patients with metastatic RCC. As with other new, targeted cancer agents, the future use of mTOR inhibitors will benefit from reproducible biomarkers that can be used in the clinic to identify patients most likely to respond and to document modulation of the drug target in addition to clinical response.     

PI3K/AKT/mTOR通路抑制剂在膀胱癌中的研究进展

磷脂酰肌醇3-激酶(PI3K)/AKT/哺乳动物雷帕霉素靶标(mTOR)通路在人类肿瘤的恶性转化及其随后的生长、增殖和转移中起重要作用。临床前研究表明,PI3K/AKT/mTOR通路在膀胱癌中经常被激活。因此,这一通路被认为是膀胱癌治疗干预的候选通路,针对该通路不同成分的抑制剂正处于临床开发的不同阶段。在这里,重点介绍我们对PI3K/AKT/mTOR通路的最新研究进展,并讨论以该通路为靶点的治疗药物作为膀胱癌治疗药物的发展障碍及发展潜力。