PI3K/Akt信号通路的调控与肿瘤血管生成

肿瘤对人类的生存危害极大,恶性肿瘤的治疗一直是世界性的难题。肿瘤血管生成是肿瘤赖以生长、转移的基础,受多种因子的调节。目前发现有多条信号网络参与调控肿瘤血管生成,PI3K/Akt是其中比较重要的一条信号传导途径,该通路与肿瘤的发生发展密切相关。本文介绍了PI3K/Akt信号通路的结构组成与活性调控,并重点阐述PI3K/Akt信号途径与肿瘤血管生成的关系。     

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.     

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.     

Annexin A3 gene silencing promotes myocardial cell repair through activation of the PI3K/Akt signaling pathway in rats with acute myocardial infarction

Acute myocardial infarction (AMI), as a severe consequence of coronary atherosclerotic heart disease, always contributes to the loss of myocardial cells. Mounting evidence shows that annexin protects the myocardium from ischemic injury. In this study, we examine the inhibition of annexin A3 (ANXA3) on AMI through the phosphatidylinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. We selected rats to build an AMI model which was then assigned into different groups. The hemodynamic parameters after transfection were detected by using enzyme-linked immunosorbent assay. The effect of silencing of ANXA3 on inflammatory reaction and the PI3K/Akt signaling pathway was assessed. Rats transfected with ANXA3-short hairpin RNA had alleviated hemodynamics, inflammatory reaction, decreased infarct size, α-smooth muscle actin, Collagen I, and Collagen III as well as an increased vascular endothelial growth factor. Silencing ANAX3 would promote repair and healing of myocardial tissue by activation of the PI3K/Akt signaling pathway. Collectively, our study provides evidence that the downregulation of ANXA3 promotes the repair and healing of myocardial tissues by activating the PI3K/Akt signaling pathway.     

High glucose induces alternative activation of macrophages via PI3K/Akt signaling pathway

Objective: It has been proved that lactate-4.25% dialysate could result in peritoneal fibrosis by inducing alternative activation of macrophages in our previous study, but the mechanism of high glucose-induced alternative activation has not been elucidated. This study was, therefore, to investigate the mechanism by high glucose stimuli.

Methods: In this study, Raw264.7 (murine macrophage cell line) cells were cultured and stimulated by 4.25% glucose medium, and mannitol medium was used as osmotic pressure control. Cells were harvested at 0?h, 4?h, 8?h, and 12?h to examine the expression of Arg-1, CD206, and p-Akt. After blocking PI3K by LY294002, the expression of Arg-1, CD206, and p-Akt was examined again.

Results: The expression of Arg-1 and CD206 was increased in a time-dependent manner induced by high glucose medium. On the contrary, there was mainly no Agr-1 or CD206 expressed in cells cultured in the mannitol medium with the same osmotic pressure. What’s more, Akt was phosphorylated at the eighth hour stimulated by high glucose medium, and LY294002 inhibited the expression of Arg-1 and CD206 by blocking the phosphorylation of Akt.

Conclusions: Our study indicated that high glucose rather than high osmotic pressure induced M2 phenotype via PI3K/Akt signaling pathway.     

Overexpression of microRNA-23a-5p induces myocardial infarction by promoting cardiomyocyte apoptosis through inhibited of PI3K/AKT signalling pathway

Myocardial infarction (MI) leads to cardiac remodelling and heart failure. Cardiomyocyte apoptosis is considered a critical pathological phenomenon accompanying MI, but the pathogenesis mechanism remains to be explored. MicroRNAs (miRs), with the identity of negative regulator of gene expression, exist as an important contributor to apoptosis. During the experiment of this study, MI mice models were successfully established and sequencing data showed that the expression of miR-23a-5p was significantly enhanced during MI progression. Further steps were taken and it showed that apoptosis of cardiac cells weakened as miR-23a-5p was downregulated and on the contrary that apoptosis strengthened with the overexpression of miR-23a-5p. To explore its working mechanisms, bioinformatics analysis was conducted by referring to multi-databases to predict the targets of miR-23a-5p. Further analysis suggested that those downstream genes enriched in several pathways, especially in the PI3K/Akt singling pathway. Furthermore, it demonstrated that miR-23a-5p was negatively related to the phosphorylation of PI3K/Akt, which plays a critical role in triggering cell apoptosis during MI. Recilisib-activated PI3K/Akt singling pathway could restrain apoptosis from inducing miR-23a-5p overexpression, and Miltefosine-blocked PI3K/Akt singling pathway could restrict apoptosis from inhibiting miR-23a-5p reduction. In conclusion, these findings revealed the pivotal role of miR-23a-5p-PI3K/Akt axis in regulating apoptosis during MI, introducing this novel axis as a potential indicator to detect ischemic heart disease and it could be used for therapeutic intervention.     

Autophagy participates in the protection role of 1,25-dihydroxyvitamin D3 in acute myocardial infarction via PI3K/AKT/mTOR pathway

Vitamin D deficiency is associated with acute myocardial infarction (AMI); thus we aimed to explore improvement effects of 1,25-dihydroxyvitamin D3 (VD3) on the AMI and its potential mechanism. AMI models were constructed using male C57/BL6J mice and randomly treated with normal saline or VD3, using sham rats as control. Heart functions, myocardial damage, apoptosis, and inflammation were evaluated. Cardiomyocytes isolated from 3-day-old suckling mice were used for in vitro verification. After VD3 treatment, AMI-induced cardiac dysfunction was reversed with better cardiac function parameters. VD3 treatment reduced inflammatory cell infiltration and myocardial infarction area accompanied by the reduction of inflammatory factors and myocardial infarction markers compared with the AMI group. VD3 treatment obviously alleviated AMI-induced myocardial apoptosis, along with Bcl-2 upregulation and downregulation of caspase-3, caspase-9, and Bax. Both in vivo and in vitro experiments revealed that VD3 enhanced the expression of LC3II and Beclin-1 and decreased soluble p62. Furthermore, VD3 enhanced the AMI-caused inhibition of PI3K, p-AKT, and p-mTOR expression, which was conversely reversed by the addition of 3-methyladenine in vitro. The study highlights the improvement effects of VD3 on cardiac functions. We proposed a potential mechanism that VD3 protects against myocardial damage, inflammation, and apoptosis by promoting autophagy through PI3K/AKT/mTOR pathway.     

Magnolol induces apoptosis via inhibiting the EGFR/PI3K/Akt signaling pathway in human prostate cancer cells

We observed that treatment of prostate cancer cells for 24 h with magnolol, a phenolic component extracted from the root and stem bark of the oriental herb Magnolia officinalis, induced apoptotic cell death in a dose‐ and time‐dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in magnolol‐treated cells. Treatment of PC‐3 cells with an apoptosis‐inducing concentration of magnolol (60 µM) resulted in a rapid decrease in the level of phosphorylated Akt leading to inhibition of its kinase activity. Magnolol treatment (60 µM) also caused a decrease in Ser(¹³⁶) phosphorylation of Bad (a proapoptotic protein), which is a downstream target of Akt. Protein interaction assay revealed that Bcl‐xL, an anti‐apoptotic protein, was associated with Bad during treatment with magnolol. We also observed that during treatment with magnolol, translocation of Bax to the mitochondrial membrane occurred and the translocation was accompanied by cytochrome c release, and cleavage of procaspase‐8, ‐9, ‐3, and poly(ADP‐ribose) polymerase (PARP). Similar results were observed in human colon cancer HCT116Bax^+/? cell line, but not HCT116Bax^?/? cell line. Interestingly, at similar concentrations (60 µM), magnolol treatment did not affect the viability of normal human prostate epithelial cell (PrEC) line. We also observed that apoptotic cell death by magnolol was associated with significant inhibition of pEGFR, pPI3K, and pAkt. These results suggest that one of the mechanisms of the apoptotic activity of magnolol involves its effect on epidermal growth factor receptor (EGFR)‐mediated signaling transduction pathways. J. Cell. Biochem. 106: 1113–1122, 2009. © 2009 Wiley‐Liss, Inc.     

Erianin induces triple-negative breast cancer cells apoptosis by activating PI3K/Akt pathway

Background: Triple-negative breast cancer (TNBC) is a refractory subtype of breast cancer, 25–30% of which have dysregulation in the PI3K/AKT pathway. The present study investigated the anticancer effect of erianin on TNBC cell line and its underlying mechanism.Methods: After treatment with erianin, MTT assay was employed to determine the MDA-MB-231 and EFM-192A cell proliferation, the nucleus morphological changes were observed by DAPI staining. The cell cycle and apoptotic proportion were detected by flow cytometry. Western blot was performed to determine the cell cycle and apoptosis-related protein expression and PI3K pathways. Finally, the antiproliferative activity of erianin was further confirmed by adding or not adding PI3K agonists SC79.Results: Erianin inhibited the proliferation of MDA-MB-231 and EFM-192A cells in a dose-dependent manner, the IC₅₀ were 70.96 and 78.58 nM, respectively. Erianin could cause cell cycle arrest at the G₂/M phase, and the expressions of p21 and p27 were up-regulated, while the expressions of CDK1 and Cyclin B1 were down-regulated. Erianin also induced apoptosis via the mitochondrial pathway, with the up-regulation of the expression of Cyto C, PARP, Bax, active form of Caspase-3, and Caspase-9. Furthermore, p-PI3K and p-Akt expression were down-regulated by erianin. After co-incubation with SC79, the cell inhibition rate of erianin was decreased, which further confirmed that the attenuated PI3K/Akt pathway was relevant to the pro-apoptotic effect of erianin.Conclusions: Erianin can inhibit the proliferation of TNBC cells and induce cell cycle arrest and apoptosis, which may ascribe to the abolish the activation of the PI3K/Akt pathway.     

Sulodexide attenuates endoplasmic reticulum stress induced by myocardial ischaemia/reperfusion by activating the PI3K/Akt pathway

Acute myocardial ischaemia/reperfusion (MI/R) injury causes severe arrhythmias with a high rate of lethality. Extensive research focus on endoplasmic reticulum (ER) stress and its dysfunction which leads to cardiac injury in MI/R Our study evaluated the effects of sulodexide (SDX) on MI/R by establishing MI/R mice models and in vitro oxidative stress models in H9C2 cells. We found that SDX decreases cardiac injury during ischaemia reperfusion and decreased myocardial apoptosis and infarct area, which was paralleled by increased superoxide dismutase and reduced malondialdehyde in mice plasm, increased Bcl‐2 expression, decreased BAX expression in a mouse model of MI/R. In vitro, SDX exerted a protective effect by the suppression of the ER stress which induced by tert‐butyl hydroperoxide (TBHP) treatment. Both of the in vivo and in vitro effects were involved in the phosphatidylinositol 3‐kinase (PI3K)/Akt signalling pathway. Inhibition of PI3K/Akt pathway by specific inhibitor, LY294002, partially reduced the protective effect of SDX. In short, our results suggested that the cardioprotective role of SDX was related to the suppression of ER stress in mice MI/R models and TBHP‐induced H9C2 cell injury which was through the PI3K/Akt signalling pathway.     

Mechanism of salidroside relieving the acute hypoxia-induced myocardial injury through the PI3K/Akt pathway

ObjectiveThe objective was to investigate the anti-inflammatory effects of salidroside through the PI3K/Akt signaling pathway and its protective effects on acute hypoxia-induced myocardial injury in rats.MethodsA total of 24 healthy Sprague-Dawley male rats were selected as the experimental subjects. All rats were divided into 4 groups by using the random number table method, with 6 rats in each group. The groups included the normal control group, the salidroside group, the hypobaric hypoxia group, and the hypobaric hypoxia + salidroside group. Rats in the salidroside group were fed in the original animal laboratory and were intragastrically administered with salidroside every morning at a dosage of 35 mg/kg. Rats in the normal control group were intragastrically administered with an equal dosage of saline. Rats in the hypobaric hypoxia + salidroside group were intragastrically administered with salidroside every morning at a dosage of 35 mg/kg, who were fed in the hypoxic experiment module for animals. The altitude was increased to 4000 m, and the rats were kept in the module for 24 h. Rats in the hypobaric hypoxia group were intragastrically administered with an equal dosage of saline in the same environment, and the altitude was increased to 4000 m after administration. Parameters of blood gas analysis, histopathological changes in cardiac tissues, cardiac indexes, and inflammatory factors IL-6 and TNF-α levels of rats in groups were compared.Results1. The cardiac indexes of rats in groups were compared. The differences between the hypobaric hypoxia group and the hypobaric hypoxia + salidroside group were statistically significant (P < 0.05). 2. The results of blood gas analysis of rats in groups were compared. The differences between the hypobaric hypoxia group and the hypobaric hypoxia + salidroside group were significantly different (P < 0.05). 3. In the hypobaric hypoxia group, the myocardial cells of rats were arranged disorderly and shaped differently, with cases such as edema, degeneration, necrosis, nucleus pyknosis, and massive infiltration of inflammatory cells. In the hypobaric hypoxia + salidroside group, the above-mentioned pathological changes in myocardial cells were relieved. 4. Compared with the hypobaric hypoxia group, in the hypobaric hypoxia + salidroside group, the concentrations of IL-6 and TNF-α in rats decreased apparently, and the differences were statistically significant (P < 0.05).ConclusionSalidroside had the repairing and protective effects on the hypobaric hypoxia-induced myocardial injuries in rats. The application of salidroside could reduce the inflammatory responses of rats with hypobaric hypoxia-induced myocardial injuries through PI3K/Akt signaling pathway, thereby protecting the myocardial cells.     

FGFRL1 affects chemoresistance of small‐cell lung cancer by modulating the PI3K/Akt pathway via ENO1

Fibroblast growth factor receptor‐like 1 (FGFRL1), a member of the FGFR family, has been demonstrated to play important roles in various cancers. However, the role of FGFRL1 in small‐cell lung cancer (SCLC) remains unclear. Our study aimed to investigate the role of FGFRL1 in chemoresistance of SCLC and elucidate the possible molecular mechanism. We found that FGFRL1 levels are significantly up‐regulated in multidrug‐resistant SCLC cells (H69AR and H446DDP) compared with the sensitive parental cells (H69 and H446). In addition, clinical samples showed that FGFRL1 was overexpressed in SCLC tissues, and high FGFRL1 expression was associated with the clinical stage, chemotherapy response and survival time of SCLC patients. Knockdown of FGFRL1 in chemoresistant SCLC cells increased chemosensitivity by increasing cell apoptosis and cell cycle arrest, whereas overexpression of FGFRL1 in chemosensitive SCLC cells produced the opposite results. Mechanistic investigations showed that FGFRL1 interacts with ENO1, and FGFRL1 was found to regulate the expression of ENO1 and its downstream signalling pathway (the PI3K/Akt pathway) in SCLC cells. In brief, our study demonstrated that FGFRL1 modulates chemoresistance of SCLC by regulating the ENO1‐PI3K/Akt pathway. FGFRL1 may be a predictor and a potential therapeutic target for chemoresistance in SCLC.     

Rotavirus-encoded virus-like small RNA triggers autophagy by targeting IGF1R via the PI3K/Akt/mTOR pathway

Rotaviruses are double-stranded RNA viruses that are a major cause of viral diarrhea in infants. Examining virus–host cell interaction is important for elucidating mechanisms of virus proliferation in host cells. Viruses can create an environment that promotes their survival and self-proliferation by encoding miRNAs or miRNA-like molecules that target various host cell. However, it remains unclear whether RNA viruses encode viral miRNAs, and their regulation mechanisms are largely unknown. We previously performed deep sequencing analysis to investigate rotavirus-encoded miRNAs, and identified the small RNA molecule Chr17_1755, which we named RV-vsRNA1755. In our present study, we determined that RV-vsRNA1755 is encoded by the rotavirus NSP4 gene and that it targets the host cell IGF1R, which is part of the PI3K/Akt pathway. We further explored the biological characteristics and functions of RV-vsRNA1755.Our results suggest that rotavirus adapts to manipulate PI3K/Akt signaling at early phases of infection. RV-vsRNA1755 targets IGF1R, blockading the PI3K/Akt pathway and triggering autophagy, but it ultimately inhibits autophagy maturation. A mechanism through which rotavirus encodes a virus-like small RNA (RV-vsRNA1755) that triggers autophagy by targeting the host cell IGF1R gene was revealed. These data provide a theoretical basis for therapeutic drug screening targeting RV-vsRNA1755.     

沉默脂肪细胞增强子结合蛋白2通过PI3K/Akt途径抑制肝癌细胞增殖和迁移

脂肪细胞增强子结合蛋白2(AEBP2)作为多梳抑制复合物2(PRC2)的组成蛋白质,参与多种肿瘤细胞的增殖和迁移,然而其在肝癌中的作用尚不清楚。本研究基于UALCAN和Kaplan-Meier Plotter数据库分析发现,AEBP2在肝癌组织中高表达,并且与患者的不良预后呈正相关。实时荧光定量PCR和蛋白质印迹结果证实,AEBP2在肝癌细胞中的表达高于正常肝细胞。在HepG2和Huh-7细胞中转染AEBP2 siRNA,平板克隆、CCK-8、流式细胞术、划痕愈合和Transwell结果显示,沉默AEBP2可以抑制肝癌细胞增殖、迁移和侵袭,并促进细胞凋亡(P＜0.05)。免疫荧光检测和蛋白质印迹结果显示,沉默AEBP2能够抑制肝癌细胞上皮-间质转化(EMT)(P＜0.05)。生物信息学分析结果表明,AEBP2参与调控PI3K/Akt信号通路。蛋白质印迹结果证实,沉默AEBP2能下调PI3K、p-AKT (S473)、mTOR、MMP-2和MMP-9的蛋白质表达水平(P＜0.05)。此外,沉默AEBP2对HepG2细胞迁移和侵袭的影响可被PI3K/Akt通路激动剂胰岛素样生长因子1(IGF-1)部分逆转(P＜0.01)。综上所述,AEBP2可能通过调节PI3K/Akt途径促进肝癌细胞增殖和迁移。本研究为AEBP2在肝癌中的作用提供理论依据。     

Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway

Tamoxifen (TAM) resistance has indicated a significant challenge during endocrine therapy for hormone-sensitive breast cancer. Thus, it is significant to elucidate the molecular events endowing TAM resistance to endocrine therapy. In this study, we found that epithelial-mesenchymal transition (EMT) was an important event to confer TAM resistance, and attenuating EMT by elevating connexin (Cx) 43 expression could reverse TAM resistance. Specifically, Cx43 overexpression improved TAM sensitivity, while Cx43 depletion facilitated TAM insensitivity by modulating EMT in T47D TAM-resistant and -sensitive cells, and transplanted xenografts. Importantly, we found a novel reciprocal regulation between Cx43 and c-Src/PI3K/Akt pathway contributing to EMT and TAM resistance in breast cancer. Moreover, we identified that Cx43 deficiency was significantly correlated with poor relapse-free survival in patients undergoing TAM treatment. Therefore, Cx43 represents a prognostic marker and an attractive target for breast cancer treatments. Therapeutic strategies designed to increase or maintain Cx43 function may be beneficial to overcome TAM resistance.