缺氧诱导因子1与PI3K/Akt/mTOR信号转导通路

缺氧诱导因子1（HIF-1）是参与缺氧调节的核心因子,可调控一系列缺氧诱导基因的表达,与机体许多生理和病理过程也密切相关。尽管一些研究显示缺氧和非缺氧性刺激可通过PI3K/Akt/mTOR信号途径诱导HIF-1的表达和活性,PI3K信号途径是否参与对HIF-1的调节仍然是个有争议的研究热点。明确HIF-1和PI3K的相互作用关系,能进一步为肿瘤等相关疾病的防治提供新的思路和方法。本文主要就HIF-1和PI3K/Akt/mTOR关系作一简要综述。     

mTOR信号途径与肿瘤

mTOR信号途径是最近新出现的细胞内重要信号途径,该途径在进化上高度保守,主要通过控制蛋白合成来调节细胞生长。现发现人体某些错构瘤综合征和恶性肿瘤存在mTOR信号途径的异常激活,雷帕霉素及其衍生物是mTOR信号特异性的抑制荆。这些新发现对了解细胞的生长调控和肿瘤的靶向性治疗具有重要意义。     

活性氧类与mTOR信号通路

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是整合细胞内外各种信号,调节蛋白质翻译与细胞生长增殖等多种生理活动的中心信号分子。活性氧类(reactive oxygen species,ROS)作为第二信使分子,可介导多种细胞信号通路并发挥广泛的生理效应。近年的研究发现ROS可通过一定的途径激活或抑制mTOR通路。而作为反馈调节,mTOR通路活性的轻度上调可促进细胞抗氧化物质的生成,而过度激活则会促进ROS生成,并增加细胞对氧化应激的敏感性,形成正反馈。本文将ROS与mTOR之间相互调节与相互作用的特点及机制的研究进展作一综述。     

Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy

Adenosine monophosphate-activated protein kinase (AMPK) acts as a major sensor of cellular energy status in cancers and is critically involved in cell sensitivity to anticancer agents. Here, we showed that AMPK was inactivated in lymphoma and related to the upregulation of the mammalian target of rapamycin (mTOR) pathway. AMPK activator metformin potentially inhibited the growth of B- and T-lymphoma cells. Strong antitumor effect was also observed on primary lymphoma cells while sparing normal hematopoiesis ex vivo. Metformin-induced AMPK activation was associated with the inhibition of the mTOR signaling without involving AKT. Moreover, lymphoma cell response to the chemotherapeutic agent doxorubicin and mTOR inhibitor temsirolimus was significantly enhanced when co-treated with metformin. Pharmacologic and molecular knock-down of AMPK attenuated metformin-mediated lymphoma cell growth inhibition and drug sensitization. In vivo, metformin induced AMPK activation, mTOR inhibition and remarkably blocked tumor growth in murine lymphoma xenografts. Of note, metformin was equally effective when given orally. Combined treatment of oral metformin with doxorubicin or temsirolimus triggered lymphoma cell autophagy and functioned more efficiently than either agent alone. Taken together, these data provided first evidence for the growth-inhibitory and drug-sensitizing effect of metformin on lymphoma. Selectively targeting mTOR pathway through AMPK activation may thus represent a promising new strategy to improve treatment of lymphoma patients.     

The role of mTOR signaling pathway in spinal cord injury

The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in multiple cellular functions, such as cell metabolism, proliferation and survival. Many previous studies have shown that mTOR regulates both neuroprotective and neuroregenerative functions in trauma and various diseases in the central nervous system (CNS). Recently, we reported that inhibition of mTOR using rapamycin reduces neural tissue damage and locomotor impairment after spinal cord injury (SCI) in mice. Our results demonstrated that the administration of rapamycin at four hours after injury significantly increases the activity of autophagy and reduces neuronal loss and cell death in the injured spinal cord. Furthermore, rapamycin-treated mice show significantly better locomotor function in the hindlimbs following SCI than vehicle-treated mice. These findings indicate that the inhibition of mTOR signaling using rapamycin during the acute phase of SCI produces neuroprotective effects and reduces secondary damage at lesion sites. However, the role of mTOR signaling in injured spinal cords has not yet been fully elucidated. Various functions are regulated by mTOR signaling in the CNS, and multiple pathophysiological processes occur following SCI. Here, we discuss several unresolved issues and review the evidence from related articles regarding the role and mechanisms of the mTOR signaling pathway in neuroprotection and neuroregeneration after SCI.     

The role of mTOR signaling pathway in spinal cord injury

The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in multiple cellular functions, such as cell metabolism, proliferation and survival. Many previous studies have shown that mTOR regulates both neuroprotective and neuroregenerative functions in trauma and various diseases in the central nervous system (CNS). Recently, we reported that inhibition of mTOR using rapamycin reduces neural tissue damage and locomotor impairment after spinal cord injury (SCI) in mice. Our results demonstrated that the administration of rapamycin at four hours after injury significantly increases the activity of autophagy and reduces neuronal loss and cell death in the injured spinal cord. Furthermore, rapamycin-treated mice show significantly better locomotor function in the hindlimbs following SCI than vehicle-treated mice. These findings indicate that the inhibition of mTOR signaling using rapamycin during the acute phase of SCI produces neuroprotective effects and reduces secondary damage at lesion sites. However, the role of mTOR signaling in injured spinal cords has not yet been fully elucidated. Various functions are regulated by mTOR signaling in the CNS, and multiple pathophysiological processes occur following SCI. Here, we discuss several unresolved issues and review the evidence from related articles regarding the role and mechanisms of the mTOR signaling pathway in neuroprotection and neuroregeneration after SCI.     

mTOR信号通路与调节

哺乳动物雷帕霉素靶蛋白mTOR是一种非典型丝氨酸／苏氨酸蛋白激酶,可整合细胞外信号,磷酸化下游靶蛋白核糖体p70S6激酶,如S6K1及4E—BP1,影响转录与翻译,从而参与调控细胞生长、增殖等过程。近年来研究发现,调控mTOR通路可以干预某些疾病的病理过程。mTOR研究的新发现,可望为今后相关疾病的治疗提供新的靶点。     

Silencing of microRNA-27a facilitates autophagy and apoptosis of melanoma cells through the activation of the SYK-dependent mTOR signaling pathway

Melanoma is considered as an aggressive neoplastic transformation and featured with high metastatic potential. Although some studies have provided targets for novel therapeutic interventions, clinical development of targeted drugs for melanoma still remains obscure. Therefore, this study aims to identify the role of microRNA-27a (miR-27a) in autophagy and apoptosis of melanoma cells in regulating spleen tyrosine kinase (SYK)-mediated the mammalian target of rapamycin (mTOR) signaling pathway. A microarray-based analysis was made to screen differentially expressed genes and predict target miRNA. Melanoma specimens were collected with pigmented nevus as a control. Melanoma cell line Mel-RM was treated with miR-27a inhibitor or pcDNA-SYK to prove their effects on autophagy and apoptosis of melanoma cells. The volume change and tumor mass of nude mice in each group were detected by the tumorigenesis assay. Microarray-based analysis results showed that SYK was lowly expressed in melanoma cells and may be regulated by miR-27a. Besides, miR-27a expression was increased whereas SYK expression was decreased in melanoma tissues. Meanwhile, miR-27a was positively correlated with tumor stage and lymph node metastasis of melanoma tissues. Furthermore, miR-27a targeted SYK and silencing of miR-27a or overexpression of SYK cells promoted autophagy and apoptosis of melanoma cells and reduced their tumorigenic ability in vivo. In conclusion, this study proves that silencing of miR-27a facilitates autophagy and apoptosis of melanoma cells by upregulating SYK expression and activating the mTOR signaling pathway. The finding offers new ideas for the clinical development of melanoma.     

Virtual screening of naphthoquinone analogs for potent inhibitors against the cancer-signaling PI3K/AKT/mTOR pathway

The PI3K/AKT/mTOR pathway is one of the most commonly disrupted signaling pathways that plays a role in the development and pathogenicity of multiple cancers. Therefore, the critical proteins of this pathway have been targeted for anticancer therapy. The scientific community has increasingly been realizing the anti-cancer therapeutic potential of naphthoquinone analogs. These compounds constitute a major class of diverse sets of plant metabolites, which include various natural products and synthetic compounds with proven anticancer activity. The current study involved structural computational biology approaches to explore compounds from a diverse pool of naphthoquinone analogs that can inhibit key cancer-signaling proteins phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT), and mammalian target of rapamycin (mTOR). The novel compound identified commonly among the top 10 dock score lists of PI3K, AKT, and mTOR was selected for further study and proposed as a potential inhibitor of the 3 cancer-signaling proteins and an anticancer agent. Further, to check the docking accuracy and potential of the compound, post docking analyses, namely, binding comparison with the native ligand, the role of the interacting residue role in binding, predicted binding energy and dissociation constant calculations, etc., were performed. All these measures showed good-quality binding, and thus provide weight to our prediction of the novel compound as a pan PI3K/AKT/mTOR inhibitor and an anticancer agent. Finally, to compare the binding and similarity in the active sites of the 3 protein kinases, a ligand-based active site alignment was performed and analyzed. Thus, the study proposed a novel naphthoquinone analog as a potential anticancer drug, and provided comparative structural insight into its binding to the 3 protein kinases.     

脂肪组织中自噬信号通路及其功能

细胞自噬是一种真核生物中高度保守的代谢过程,包括巨自噬、微自噬以及分子伴侣介导的自噬等。自噬过程可以清除受损的细胞器,降解糖原、脂类和蛋白质等生物大分子物质,供细胞重新利用,维持细胞内代谢平衡。自噬障碍与多种疾病的病理发生过程息息相关,包括肿瘤、2型糖尿病、肥胖、骨骼肌病以及神经退行性疾病等。脂肪组织是人体脂质储存的重要场所,广泛分布于全身各处,如内脏和皮下等。脂肪组织通过储存冗余脂肪并分泌脂肪因子,防止脂肪的异位堆积和脂毒性的发生,维持机体的脂质稳态。近期的许多研究表明,自噬进程深度参与脂肪细胞的细胞分化与能量代谢。因此,深入探究脂肪组织自噬过程与机体脂质稳态的调控关系,有利于揭示机体脂质平衡的内在机制,为新型药物靶点的开发提供扎实的理论依据和数据支持。本文就近年来关于自噬影响脂肪组织脂质代谢的最新研究进展作一综述。     

Noradrenaline enhances the expression of the neuronal monocarboxylate transporter MCT2 by translational activation via stimulation of PI3K/Akt and the mTOR/S6K pathway

Monocarboxylate transporter 2 (MCT2) expression is up-regulated by noradrenaline (NA) in cultured cortical neurons via a putative but undetermined translational mechanism. Western blot analysis showed that p44/p42 mitogen-activated protein kinase (MAPK) was rapidly and strongly phosphorylated by NA treatment. NA also rapidly induced serine/threonine protein kinase from AKT virus (Akt) phosphorylation but to a lesser extent than p44/p42 MAPK. However, Akt activation persisted over a longer period. Similarly, NA induced a rapid and persistent phosphorylation of mammalian target of rapamycin (mTOR), a kinase implicated in the regulation of translation in the central nervous system. Consistent with activation of the mTOR/S6 kinase pathway, phosphorylation of the ribosomal S6 protein, a component of the translation machinery, could be observed upon treatment with NA. In parallel, it was found that the NA-induced increase in MCT2 protein was almost completely blocked by LY294002 (phosphoinositide 3-kinase inhibitor) as well as by rapamycin (mTOR inhibitor), while mitogen-activated protein kinase kinase and p38 MAPK inhibitors had much smaller effects. Taken together, these data reveal that NA induces an increase in neuronal MCT2 protein expression by a mechanism involving stimulation of phosphoinositide 3-kinase/Akt and translational activation via the mTOR/S6 kinase pathway. Moreover, considering the role of NA in synaptic plasticity, alterations in MCT2 expression as described in this study might represent an adaptation to face energy demands associated with enhanced synaptic transmission.     

mTOR信号通路与肾上腺肿瘤发生发展的关系进展

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,m TOR)是一种丝/苏氨酸蛋白激酶,是细胞内调控生长、增殖的中心信号分子,与肿瘤发生、发展关系密切.近年发现,m TOR信号通路在肾上腺肿瘤的发生发展中扮演重要角色.许多研究证实,PI3K/Akt/m TOR信号通路的关键蛋白Akt、m TOR、S6K1、4EB-P1的磷酸化水平在肾上腺皮质癌(adrenocortical carcinoma,ACC)和嗜铬细胞瘤(pheochromocytomas,PCC)中均明显高于正常肾上腺组织,且可能与肾上腺肿瘤的恶性转化相关.胰岛素样生长因子2基因的杂合性缺失、PTEN的生殖系突变、微小RNA表达异常均可激活PI3K/Akt/m TOR信号通路,使得血管内皮生长因子、细胞周期蛋白等分子过表达,从而产生抑凋亡、促增殖、促血管形成等效应,使组织呈现出肿瘤特征,并促进肿瘤的侵袭和转移.目前,细胞和动物模型研究已证实m TOR抑制剂对ACC与PCC有良好的疗效,且联合其他抗癌药物治疗效果更佳,这给肾上腺肿瘤患者的治疗带来了新的希望.本文总结了近年来m TOR信号通路与肾上腺肿瘤发生、发展的关系进展,希望为肾上腺肿瘤的机制研究及临床治疗提供实验室依据.     

The role of microRNAs involved in PI3-kinase signaling pathway in colorectal cancer

In recent decades, cancer has been one of the most important concerns of the human community, which affects human life from many different ways, such as breast, lung, colorectal, prostate, and other cancers. Colorectal cancer is one of the most commonly diagnosed cancers in the world that has recently been introduced as the third leading cause of cancer deaths in the world. microRNAs have a very crucial role in tumorgenesis and prevention of cancer, which plays a significant role with influencing various factors through different signaling pathways. Phosphoinositide 3 (PI3)-kinase/AKT is one of the most important signaling pathways involved in the control and growth of tumor in colorectal cancer, through important proteins of this pathway, such as PTEN and AKT, that they can perform specific influence on this process. Our effort in this study is to collect microRNAs that act as tumor suppressors and oncomirs in this cancer through PI3-kinase/AKT signaling pathway.     

PI3K/Akt/mTOR信号通路及临床相关肿瘤抑制剂

哺乳动物雷帕霉素靶（mTOR）和蛋白激酶B（Akt/PKB）与肿瘤发生的密切关系已被广泛地认可.mTOR是一种丝/苏氨酸激酶,可以通过影响mRNA转录、代谢、自噬等方式调控细胞的生长.它既是PI3K的效应分子,也可以是PI3K的反馈调控因子.mTORC1 和mTORC2是mTOR的两种不同复合物. 对雷帕霉素敏感的mTORC1受到营养、生长因子、能量和应激4种因素的影响.生长因子通过PI3K/Akt信号通路调控mTORC1是最具特征性调节路径.而mTORC2最为人熟知的是作为Akt473磷酸化位点的上游激酶. 同样,Akt/PKB在细胞增殖分化、迁移生长过程中发挥着重要作用. 随着Thr308和Ser473两个位点激活,Akt/PKB也得以全面活化.因此,mTORC2-Akt-mTORC1的信号通路在肿瘤形成和生长中是可以存在的.目前临床肿瘤治疗中,PI3K/Akt/mTOR是重要的靶向治疗信号通路.然而,仅抑制mTORC1活性,不是所有的肿瘤都能得到预期控制.雷帕霉素虽然能抑制mTORC1,但也能反馈性地增加PI3K信号活跃度,从而影响治疗预后.近来发现的第二代抑制剂可以同时抑制mTORC1/2和PI3K活性,这种抑制剂被认为在肿瘤治疗上颇具前景.本综述着重阐述了PI3K/Akt/mTOR信号通路的传导、各因子之间的相互调控以及相关抑制剂的发展.