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.     

Melatonin protects against methotrexate hepatotoxicity in young rats: Impact of PI3K/Akt/mTOR signaling

With the improvement in children's acute lymphoblastic leukemia (ALL) care, the survival rate in children ALL has improved much. Methotrexate (MTX) plays an essential role in the success of children's ALL treatment. Since hepatotoxicity is commonly reported in individuals treated with intravenous or oral MTX, our study further examined the hepatic effect following intrathecal MTX treatment, which is an essential treatment for leukemia patients. Specifically, we examined the pathogenesis of MTX hepatotoxicity in young rats and explored the impact of melatonin treatment in protection against MTX hepatotoxicity. Successfully, we found that melatonin was able to protect against MTX hepatotoxicity.     

Duvelisib attenuates bleomycin-induced pulmonary fibrosis via inhibiting the PI3K/Akt/mTOR signalling pathway

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that seriously threatens the health of patients. The pathogenesis of IPF is still unclear, and there is a lack of effective therapeutic drugs. Myofibroblasts are the main effector cells of IPF, leading to excessive deposition of extracellular matrix (ECM) and promoting the progression of fibrosis. Inhibiting the excessive activation and relieving autophagy blockage of myofibroblasts is the key to treat IPF. PI3K/Akt/mTOR pathway plays a key regulatory role in promoting fibroblast activation and autophagy inhibition in lung fibrosis. Duvelisib is a PI3K inhibitor that can simultaneously inhibit the activities of PI3K-δ and PI3K-γ, and is mainly used for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma tumour (SLL). In this study, we aimed to examine the effects of Duvelisib on pulmonary fibrosis. We used a mouse model of bleomycin-induced pulmonary fibrosis to evaluate the effects of Duvelisib on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of Duvelisib in lung fibroblasts in vitro. The in vivo experiments showed that Duvelisib significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function. In vitro and in vivo pharmacological experiments showed that Duvelisib dose-dependently suppressed lung fibroblast activation and improved autophagy inhibition by inhibiting the phosphorylation of PI3K, Akt and mTOR. Our results indicate that Duvelisib can alleviate the severity of pulmonary fibrosis and provide potential drugs for the treatment of pulmonary fibrosis.     

Follistatin could promote the proliferation of duck primary myoblasts by activating PI3K/Akt/mTOR signalling

FST (follistatin) is essential for skeletal muscle development, but the intracellular signalling networks that regulate FST-induced effects are not well defined. We sought to investigate whether FST promotes the proliferation of myoblasts through the PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B)/mTOR (mammalian target of rapamycin) signalling. In the present study, we transfected the pEGFP-duFST plasmid and added PI3K and mTOR inhibitors to the medium of duck primary myoblasts. Then, we analysed the cellular phenotypic changes that occurred and analysed the expression of target genes. The results showed that FST promoted myoblast proliferation, induced the mRNA expression of PI3K, Akt, mTOR, 70-kDa ribosomal protein S6K (S6 kinase) and the protein expression of phospho-Akt (Thr³⁰⁸), mTOR, phospho-mTOR (serine 2448), phospho-S6K (Ser⁴¹⁷), inhibited the mRNA expression of FoxO1, MuRF1 (muscle RING finger-1) and the protein expression of phospho-FoxO1 (Ser²⁵⁶). Moreover, we found that the overexpression of FST could alleviate the inhibitory effect of myoblast proliferation caused by the addition of {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, a PI3K inhibitor. Additionally, the overexpression of duck FST also relieved the inhibition of myoblast proliferation caused by the addition of rapamycin (an mTOR inhibitor) through PI3K/Akt/mTOR signalling. In light of the present results, we hypothesize that duck FST could promote myoblast proliferation, which is dependent on PI3K/Akt/mTOR signalling.     

PI3K/Akt/mTOR信号通路与自噬及肿瘤的关系

自噬是一种以胞质内出现双层膜结构包裹长寿命蛋白和细胞器的自噬体为特征的细胞“自我消化”过程,在维持细胞内稳态、发育、肿瘤发生和感染中发挥重要作用。近来,诸多研究表明,自噬作为一把“双刃剑”,对肿瘤的发生发展既有促进作用,也有抑制作用。PI3K/Akt/mTOR通路由PI3激酶(PI3K)、蛋白激酶B（PKB/Akt）和哺乳动物类雷帕霉素靶蛋白（mTOR）3个作用分子组成,是一个中心的调节机构,对肿瘤细胞的生长与增殖有促进作用,同时对自噬进行抑制。本文就PI3K/Akt/mTOR通路与自噬及肿瘤发生发展的关系作一综述。     

RhoGDI2与PI3K/Akt/mTOR信号通路在肺癌细胞中的相关性研究

目的探讨肿瘤转移相关因子RhoGDI2与PI3K/Akt/mTOR信号通路在肺癌侵袭转移过程中的作用及相关机制。方法利用PI3K/Akt/mTOR信号通路上特异性的抑制剂,采用MTT法,伤口愈合实验及侵袭实验观察不同浓度药物对肺癌95D细胞生长侵袭转移能力的影响,通过Western Blot方法观察RhoGDI2蛋白水平的变化。结果PI3K抑制剂LY294002及mTOR抑制剂Rapamycin都能抑制肺癌细胞95D的侵袭转移能力,联合应用抑制作用更强。PI3K抑制剂LY294002处理组RhoGDI2蛋白的表达量增加,且随浓度增加RhoGDI2蛋白表达也增加。mTOR抑制剂Rapamycin组,在低浓度时增加RhoGDI2蛋白的表达,但增大Rapamycin的浓度,RhoGDI2蛋白的表达反而降低。低浓度LY294002组和Rapa-mycin组联合应用可以明显增加RhoGDI2蛋白的表达。结论PI3K/Akt/mTOR信号通路中Akt的活化与RhoGDI2密切相关,RhoGDI2可能直接或间接通过与Akt的相互作用参与调节肺癌的侵袭转移的过程。     

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5 years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, that is, inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention.     

PI3K/AKT/mTOR信号通路及其在卵巢癌治疗中的应用

卵巢癌是女性生殖系统常见的恶性肿瘤,发病率居于妇科恶性肿瘤第三位,死亡率居于妇科恶性肿瘤之首。目前对卵巢癌的标准治疗包括肿瘤细胞减灭术及卡铂和紫杉醇的联合化疗。PI3K/AKT/mTOR信号通路在卵巢癌的细胞增殖、侵袭、细胞周期进展、血管生成及耐药中发挥重要作用,是卵巢癌中最常发生改变的细胞内途径。本文对PI3K/AKT/mTOR信号通路及其在卵巢癌增殖和进展中的影响、PI3K/AKT/mTOR信号通路抑制剂在卵巢癌中的治疗应用做简要综述。     

Duvelisib attenuates bleomycin‐induced pulmonary fibrosis via inhibiting the PI3K/Akt/mTOR signalling pathway

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that seriously threatens the health of patients. The pathogenesis of IPF is still unclear, and there is a lack of effective therapeutic drugs. Myofibroblasts are the main effector cells of IPF, leading to excessive deposition of extracellular matrix (ECM) and promoting the progression of fibrosis. Inhibiting the excessive activation and relieving autophagy blockage of myofibroblasts is the key to treat IPF. PI3K/Akt/mTOR pathway plays a key regulatory role in promoting fibroblast activation and autophagy inhibition in lung fibrosis. Duvelisib is a PI3K inhibitor that can simultaneously inhibit the activities of PI3K‐δ and PI3K‐γ, and is mainly used for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma tumour (SLL). In this study, we aimed to examine the effects of Duvelisib on pulmonary fibrosis. We used a mouse model of bleomycin‐induced pulmonary fibrosis to evaluate the effects of Duvelisib on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of Duvelisib in lung fibroblasts in vitro. The in vivo experiments showed that Duvelisib significantly alleviated bleomycin‐induced collagen deposition and improved pulmonary function. In vitro and in vivo pharmacological experiments showed that Duvelisib dose‐dependently suppressed lung fibroblast activation and improved autophagy inhibition by inhibiting the phosphorylation of PI3K, Akt and mTOR. Our results indicate that Duvelisib can alleviate the severity of pulmonary fibrosis and provide potential drugs for the treatment of pulmonary fibrosis.     

Effects of PI3K catalytic subunit and Akt isoform deficiency on mTOR and p70S6K activation in myoblasts

The PI3K/Akt/mTOR signaling pathway is critical for cellular growth and survival in skeletal muscle, and is activated in response to growth factors such as insulin-like growth factor-I (IGF-I). We found that in C2C12 myoblasts, deficiency of PI3K p110 catalytic subunits or Akt isoforms had distinct effects on phosphorylation of mTOR and p70S6K. siRNA-mediated knockdown of PI3K p110α, p110β, and simultaneous knockdown of p110α and p110β resulted in increased basal and IGF-I-stimulated phosphorylation of mTOR S2448 and p70S6K T389; however, phosphorylation of S6 was reduced in p110β-deficient cells, possibly due to reductions in total S6 protein. We found that IGF-I-stimulated Akt1 activity was enhanced in Akt2- or Akt3-deficient cells, and that knockdown of individual Akt isoforms increased mTOR/p70S6K activation in an isoform-specific fashion. Conversely, levels of IGF-I-stimulated p70S6K phosphorylation in cells simultaneously deficient in both Akt1 and Akt3 were increased beyond those seen with loss of any single Akt isoform, suggesting an alternate, Akt-independent mechanism that activates mTOR/p70S6K. Our results collectively suggest that mTOR/p70S6K is activated in a PI3K/Akt-dependent manner, but that in the absence of p110α or Akt, alternate pathway(s) may mediate activation of mTOR/p70S6K in C2C12 myoblasts.     

PTEN Overexpression Cooperates With Lithium to Reduce the Malignancy and to Increase Cell Death by Apoptosis via PI3K/Akt Suppression in Colorectal Cancer Cells

Lithium is a well‐established non‐competitive inhibitor of glycogen synthase kinase‐3β (GSK‐3β), a kinase that is involved in several cellular processes related to cancer progression. GSK‐3β is regulated upstream by PI3K/Akt, which is negatively modulated by PTEN. The role that lithium plays in cancer is controversial because lithium can activate or inhibit survival signaling pathways depending on the cell type. In this study, we analyzed the mechanisms by which lithium can modulate events related to colorectal cancer (CRC) progression and evaluated the role that survival signaling pathways such as PI3K/Akt and PTEN play in this context. We show that the administration of lithium decreased the proliferative potential of CRC cells in a GSK‐3β‐independent manner but induced the accumulation of cells in G2/M phase. Furthermore, high doses of lithium increased apoptosis, which was accompanied by decreased proteins levels of Akt and PTEN. Then, cells that were induced to overexpress PTEN were treated with lithium; we observed that low doses of lithium strongly increased apoptosis. Additionally, PTEN overexpression reduced proliferation, but this effect was minor compared with that in cells treated with lithium alone. Furthermore, we demonstrated that PTEN overexpression and lithium treatment separately reduced cell migration, colony formation, and invasion, and these effects were enhanced when lithium treatment and PTEN overexpression were combined. In conclusion, our findings indicate that PTEN overexpression and lithium treatment cooperate to reduce the malignancy of CRC cells and highlight lithium and PTEN as potential candidates for studies to identify new therapeutic approaches for CRC treatment. J. Cell. Biochem. 117: 458–469, 2016. © 2015 Wiley Periodicals, Inc.     

Chamomile Essential Oil: Chemical Constituents and Antitumor Activity in MDA-MB-231 Cells through PI3K/Akt/mTOR Signaling Pathway

Chamomile essential oil (CEO) is extracted from chamomile and mainly used in aromatherapy. The chemical constituents and its antitumor activity on Triple-negative breast cancer (TNBC) was explored in the present study. Gas chromatography-mass spectrometry (GC/MS) was employed to analyze the chemical constituents of CEO. The cell viability, migration and invasion of TNBC cell MDA-MB-231 were measured using MTT, wound scratch and Transwell assay, respectively. The protein expression of PI3K/Akt/mTOR signaling pathway was determined by Western blot. CEO is rich in terpenoids (63.51 %), among which the identified terpenoids and their derivatives are mainly Caryophyllene (29.57 %), d-Cadinene (12.81 %), Caryophyllene oxide (14.51 %), etc. Three concentration of CEO (1, 1.5, 2 μg/mL) significantly inhibited the proliferation, migration and invasion of MDA-MB-231 cells with a dose dependent manner. Moreover, the phosphorylation of PI3K, Akt and mTOR was inhibited by CEO. The results revealed that there was abundant terpenoids in the CEO which account for 63.51 %. CEO significantly inhibited the proliferation, migration and invasion of MDA-MB-231 cells, exhibiting antitumor effect on TNBC. The antitumor effect of CEO might attribute to its inhibition on PI3K/Akt/mTOR signaling pathway. However, further study should be conducted in more TNBC cell lines and animal models to provide further evidence for TNBC treatment by CEO.     

Loss of FAM60A attenuates cell proliferation in glioma via suppression of PI3K/Akt/mTOR signaling pathways

BackgroundGlioma is a common malignant tumor of the central nervous system with a high incidence and mortality. Family with sequence similarity 60 member A (FAM60A) is a new subunit of the Sin3 deacetylase complex. The clinical significance and biologic role of FAM60A in glioma remain unclear.MethodsThe expression of FAM60A in normal glial cells, glioma cells, and five-paired gliomas, and adjacent noncancerous tissues was quantified using real-time polymerase chain reaction (PCR) and western blotting. FAM60A protein expression in 179 archived, paraffin-embedded glioma samples was analyzed using immunohistochemistry. The roles of FAM60A in glioma cell proliferation and tumorigenicity were explored in vitro and in vivo. The underlying molecular mechanisms were elucidated using Western blot assay. Serum exosomal FAM60A levels of glioma patients were detected using electron microscopy, western blot, and real-time PCR.ResultsFAM60A expression was significantly up-regulated in glioma tissues and cell lines and positively associated with a worse outcome in glioma. Knockdown of FAM60A could inhibit glioma cell proliferation and tumorigenicity in vitro and in vivo. Besides, FAM60A expression was detectable in extracted serum exosomes with a higher expression in the glioma cancer group than in the normal group.ConclusionsLoss of FAM60A attenuates cell proliferation in glioma by suppressing PI3K/Akt/mTOR signaling pathways. Therefore, FAM60A may act as a prognostic biomarker and therapeutic target for glioma.     

PI3K/Akt/mTOR signaling orchestrates the phenotypic transition and chemo-resistance of small cell lung cancer

Small cell lung cancer(SCLC) is a phenotypically heterogeneous disease with an extremely poor prognosis,which is mainly attributed to the rapid development of resistance to chemotherapy. However, the relation between the growth phenotypes and chemo-resistance of SCLC remains largely unclear. Through comprehensive bioinformatic analyses, we found that the heterogeneity of SCLC phenotype was significantly associated with different sensitivity to chemotherapy. Adherent or semiadherent SCLC cells were enriched with activation of the PI3K/Akt/mTOR pathway and were highly chemoresistant. Mechanistically,activation of the PI3K/Akt/mTOR pathway promotes the phenotypic transition from suspension to adhesion growth pattern and confers SCLC cells with chemo-resistance. Such chemo-resistance could be largely overcome by combining chemotherapy with PI3K/Akt/mTOR pathway inhibitors. Our findings support that the PI3K/Akt/mTOR pathway plays an important role in SCLC phenotype transition and chemo-resistance,which holds important clinical implications for improving SCLC treatment.     

Benzo[b]furan derivatives induces apoptosis by targeting the PI3K/Akt/mTOR signaling pathway in human breast cancer cells

The PI3K/Akt/mTOR signaling pathway plays a key regulatory function in cell survival, proliferation, migration, metabolism and apoptosis. Aberrant activation of the PI3K/Akt/mTOR pathway is found in many types of cancer and thus plays a major role in breast cancer cell proliferation. In our previous studies, benzo[b]furan derivatives were evaluated for their anticancer activity and the lead compounds identified were 26 and 36. These observations prompted us to investigate the molecular mechanism and apoptotic pathway of these lead molecules against breast cancer cells. Benzo[b]furan derivatives (26 and 36) were evaluated for their antiproliferative activity against human breast cancer cell lines MCF-7 and MDA MB-231. These compounds (26 and 36) have shown potent efficiency against breast cancer cells (MCF-7) with IC₅₀ values 0.057 and 0.051 μM respectively. Cell cycle analysis revealed that these compounds induced cell cycle arrest at G2/M phase in MCF-7 cells. Western blot analysis revealed that these compounds inhibit the PI3K/Akt/mTOR signaling pathway and induced mitochondrial mediated apoptosis in human breast cancer cells (MCF-7).     

前列腺癌雄激素受体和PI3K/Akt信号通路相互作用研究进展

前列腺癌的发生、进展依赖于雄激素,因此去势手术成为治疗晚期前列腺癌的标准疗法。但是去势后大多前列腺癌最终将转化为雄激素非依赖性前列腺癌,甚至进展为激素难治性前列腺癌,使得肿瘤的进展不受低水平雄激素的影响。即使如此,大多数激素非依赖性前列腺癌,依然阳性表达雄激素受体。因而雄激素受体在前列腺癌发生发展中起着重要作用。而PI3K/Akt信号通路能够通过维持细胞生存、抑制细胞凋亡、促进细胞代谢及血管生成等促进前列腺癌进展。本综述旨在总结前人研究,阐述雄激素受体和PI3K/Akt信号通路之间相互作用关系。研究表明Akt信号通路能够正性或者负性调控AR蛋白表达、蛋白的稳定性及其转录活性,从而维持细胞的生存、代谢。而AR即可以通过基因转录途径抑制Akt活化又能通过非转录基因途径激活Akt及其下游蛋白。因此,AR和Akt信号通路相互协同促进前列腺癌的发生及其向雄激素非依赖性前列腺癌进展。