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Apatinib suppresses the migration, invasion and angiogenesis of hepatocellular carcinoma cells by blocking VEGF and PI3K/AKT signaling pathways.

ABSTRACT: Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy worldwide with poor prognosis and high metastasis and recurrence rates. Although apatinib has been demonstrated to have potential antitumor activity in multiple solid tumors, the underlying mechanism of apatinib in HCC treatment remains to be elucidated. In the present study, apatinib were used to treat HCC cells transfected with or without VEGFR2 overexpression vectors. The proliferation of HCC cells was detected by MTT assay. The migration and invasion of HCC cells were detected by wound healing assay and Transwell assay. The ability of angiogenesis of HCC cells were detected by tube formation assay. The related protein expression levels were detected by western blotting. The present study aims to investigate the effect and potential mechanism of apatinib on the migration, invasion and angiogenesis of HCC cells. It was found that apatinib treatment significantly inhibited the proliferation, migration and invasion of Hep3b cells and suppressed angiogenesis in HUVECs. In addition, apatinib inhibited the epithelial‑mesenchymal transition of Hep3b cells by increasing the expression of the epithelial hallmarks E‑cadherin and α‑catenin and decreased the expression of the mesenchymal hallmarks N‑cadherin and vimentin. These effects were associated with the downregulation of VEGF and VEGFR2 and suppression of the PI3K/AKT signaling pathway. Thus, apatinib inhibited cell migration, invasion and angiogenesis by blocking the VEGF and PI3K/AKT pathways, supporting an effective therapeutic strategy in the treatment of HCC.

SUBMITTER: Song J

PROVIDER: S-EPMC8047914 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Celastrol Suppresses Glioma Vasculogenic Mimicry Formation and Angiogenesis by Blocking the PI3K/Akt/mTOR Signaling Pathway.

Project description:Angiogenesis and vasculogenic mimicry (VM) are thought to be the predominant processes ensuring tumor blood supply during the growth and metastasis of glioblastoma (GBM). Celastrol has potential anti-glioma effects, however the mechanisms underlying these effects remain unclarified. Recent studies have shown that the PI3K/Akt/mTOR signaling pathway is closely related to angiogenesis and VM formation. In the present study, we have demonstrated, for the first time, that celastrol eliminated VM formation by blocking this signaling pathway in glioma cells. By the treatment of celastrol, tumor growth was suppressed, tight junction and basal lamina structures in tumor microvasculature were disarranged in U87 glioma orthotopic xenografts in nude mice. Periodic acid Schiff (PAS)-CD31 staining revealed that celastrol inhibited both VM and angiogenesis in tumor tissues. Additionally, celastrol reduced the expression levels of the angiogenesis-related proteins CD31, vascular endothelial growth factor receptor (VEGFR) 2, angiopoietin (Ang) 2 and VEGFA, VM-related proteins ephrin type-A receptor (EphA) 2, and vascular endothelial (VE)-cadherin. Hypoxia inducible factor (HIF)-1α, phosphorylated PI3K, Akt, and mTOR were also downregulated by treatment with celastrol. In vitro, we further demonstrated that celastrol inhibited the growth, migration, and invasion of U87 and U251 cells, disrupted VM formation, and blocked the activity of PI3K, Akt, and mTOR. Collectively, our data suggest that celastrol inhibits VM formation and angiogenesis likely by regulating the PI3K/Akt/mTOR signaling pathway.

| S-EPMC7025498 | biostudies-literature

<i>Kochia scoparia</i> seed extract suppresses VEGF-induced angiogenesis via modulating VEGF receptor 2 and PI3K/AKT/mTOR pathways.

Project description:Context: Kochia scoparia (L.) Schrad (Amaranthaceae), known as a traditional medicine in China, Japan and Korea, is reported to have various biological activities. However, K. scoparia seed extract (KSE) functional roles on angiogenesis and prostate cancer inhibition have not been elucidated. Objective: This study elucidates the effects of KSE on vascular endothelial growth factor (VEGF)-induced angiogenesis in human umbilical vein endothelial cells (HUVECs) and inhibition of proliferation in prostate cancer cells. Materials and methods: HUVECs were treated with 10-20 µg/mL of KSE and 20-50 ng/mL of VEGF for 12-72 h. Anti-angiogenesis properties of KSE were determined by wound healing, trans-well, tube formation, rat aortic ring assay and western blotting. Prostate cancer and normal cells were incubated with 10-250 µg/mL of KSE for 24 h, and cell viability was measured by SRB assay. Phenolic compounds in KSE were analyzed using a HPLC-PDA system. Results: IC50 for cell viability of HUVECs, LNCaP, PC-3, RC-58T and RWPE-1 by KSE were 30.64, 89.25, 123.41, 141.62 and >250 µg/mL, respectively. Treatment with KSE (20 µg/mL) significantly suppressed VEGF-induced migration, invasion and capillary-like structure formation of HUVECs and microvessel sprouting from rat aortic rings. In addition, KSE down-regulated PI3K/AKT/mTOR levels and phosphorylation of VEGF receptor 2 in HUVECs. 3-OH-tyrosol (1.63 mg/g) and morin hydrate (0.17 mg/g) were identified in KSE. Conclusions: KSE inhibits angiogenesis in HUVECs as well as proliferation in human prostate cancer cells, suggesting KSE may be useful herbal medicine for preventing progression of prostate cancer and angiogenesis.

| S-EPMC6807910 | biostudies-literature

PGM1 suppresses colorectal cancer cell migration and invasion by regulating the PI3K/AKT pathway.

Project description:BackgroundPhosphoglucomutase 1 (PGM1) is known for its involvement in cancer pathogenesis. However, its biological role in colorectal cancer (CRC) has remained unknown. Here, we studied the functions and mechanisms of PGM1 in CRC.MethodsWe verified PGM-1 as a differentially expressed gene (DEG) by employing a comprehensive strategy of TCGA-COAD dataset mining and computational biology. Relative levels of PGM-1 in CRC tumors and adjoining peritumoral tissues were determined by qRT-PCR, western blotting (WB), and immunohistochemical (IHC) staining in a tissue microarray. PGM1 functions were analyzed by CCK8, EdU, colony formation, cell cycle, apoptosis, and Transwell migration and invasion assays. The influence of PGM1 was further investigated by studying tumor formation in vivo.ResultsThe levels of PGM1 mRNA and protein were both reduced in CRC tissues, and the reductions were related to CRC pathology and overall survival. PGM1 knockdown stimulated both cell proliferation and colony formation, and inhibited cell cycle arrest and apoptosis, while overexpression of PGM1 produced the opposite effects in CRC cells both in vivo and in vitro. Furthermore, the effects of PGM1 were related to the PI3K/ AKT pathway.ConclusionWe verified that PGM1 suppresses CRC progression via the PI3K/AKT pathway. These results suggest the potential for targeting PGM1 in treatment of CRC.

| S-EPMC9134613 | biostudies-literature

CK-3, A Novel Methsulfonyl Pyridine Derivative, Suppresses Hepatocellular Carcinoma Proliferation and Invasion by Blocking the PI3K/AKT/mTOR and MAPK/ERK Pathways.

Project description:Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis that highly expresses phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (ERK). The PI3K/AKT/mTOR and MAPK/ERK signaling pathways play a crucial role in HCC tumor formation, cell cycle, apoptosis and survival. However, no effective targeted therapies against these pathways is available, mainly due to the extensive and complex negative feedback loops between them. Here we used CK-3, a dual blocker of the PI3K/AKT/mTOR and MAPK/ERK pathways, against HCC cell lines to verify its anti-tumor activity in vitro. CK-3 exhibited cytotoxic activity against HCC, as demonstrated with MTT and colony formation assays. The anti-metastatic potential of CK-3 was demonstrated with wound healing and cell invasion assays. The ability of CK-3 to block both the PI3K/AKT/mTOR and MAPK/ERK pathways was also confirmed. CK-3 induced the apoptosis of Hep3B cells, while Bel7402 cells died via mitotic catastrophe (MC). Oral administration of CK-3 also inhibited the subcutaneous growth of BEL7402 cells in nude mice. Simultaneous PI3K/AKT/mTOR and MAPK/ERK pathway inhibition with CK-3 may be superior to single pathway monotherapies by inhibiting their feedback-regulation, and represents a potential treatment for HCC.

| S-EPMC8355706 | biostudies-literature

Targeting EMP3 suppresses proliferation and invasion of hepatocellular carcinoma cells through inactivation of PI3K/Akt pathway.

Project description:Epithelial membrane protein-3 (EMP3), a typical member of the epithelial membrane protein (EMP) family, is epigenetically silenced in some cancer types, and has been proposed to be a tumor suppressor gene. However, its effects on tumor suppression are controversial and its roles in development and malignancy of hepatocellular carcinoma (HCC) remain unclear. In the present study, we found that EMP3 was highly expressed in the tumorous tissues comparing to the matched normal tissues, and negatively correlated with differentiated degree of HCC patients. Knockdown of EMP3 significantly reduced cell proliferation, arrested cell cycle at G1 phase, and inhibited the motility and invasiveness in accordance with the decreased expression and activity of urokinase plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9) in HCC cells. The in vivo tumor growth of HCC was effectively suppressed by knockdown of EMP3 in a xenograft mouse model. The EMP3 knockdown-reduced cell proliferation and invasion were attenuated by inhibition of phosphatidylinositol 3-kinase (PI3K) or knockdown of Akt, and rescued by overexpression of Akt in HCC cells. Clinical positive correlations of EMP3 with p85 regulatory subunit of PI3K, p-Akt, uPA, as well as MMP-9 were observed in the tissue sections from HCC patients. Here, we elucidated the tumor progressive effects of EMP3 through PI3K/Akt pathway and uPA/MMP-9 cascade in HCC cells. The findings provided a new insight into EMP3, which might be a potential molecular target for diagnosis and treatment of HCC.

| S-EPMC4741495 | biostudies-literature

Apatinib potentiates irradiation effect via suppressing PI3K/AKT signaling pathway in hepatocellular carcinoma.

Project description:BACKGROUND:Limited effective intervention for advanced hepatocellular carcinoma (HCC) is available. This study aimed to investigate the potential clinical utility of apatinib, a highly selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase, as a radiosensitizer in the treatment of HCC. METHODS:Four human HCC cell lines SMMC-7721, MHCC-97H, HCCLM3 and Hep-3B were treated with apatinib, irradiation or combination treatment. Colony formation assay, flow cytometry and nuclear ?-H2AX foci immunofluorescence staining were performed to evaluate the efficacy of combination treatment. RNA sequencing was conducted to explore the potential mechanism. The impact of combination treatment on tumor growth was assessed by xenograft mice models. RESULTS:Colony formation assay revealed that apatinib enhanced the radiosensitivity of HCC cell lines. Apatinib suppressed repair of radiation-induced DNA double-strand breaks. Flow cytometry analysis showed that apatinib increased radiation-induced apoptosis. Apatinib radiosensitized HCC via suppression of radiation-induced PI3K/AKT pathway. Moreover, an in vivo study indicated apatinib combined with irradiation significantly decreased xenograft tumor growth. CONCLUSIONS:Our results indicate that apatinib has therapeutic potential as a radiosensitizer in HCC, and PI3K/AKT signaling pathway plays a critical role in mediating radiosensitization of apatinib.

| S-EPMC6836669 | biostudies-literature

Tanshinol inhibits the growth, migration and invasion of hepatocellular carcinoma cells via regulating the PI3K-AKT signaling pathway.

Project description:Background:Tanshinol is an active constituent of Salvia miltiorrhiza and possess anti-inflammatory, antioxidant, and anti-bacterial activity. Herein, we explored the role of tanshinol on the growth and aggressiveness of hepatocellular carcinoma (HCC) cells in vitro and in vivo. Materials and methods:The proliferation of a panel of HCC cell lines was measured using MTT assay. The expressions of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT) were detected by immunofluorescence staining and immunohistochemical assay. The levels of Bcl-2 and Bax were determined using immunoblotting assay. The secretions of matrix metalloproteinase-2 (MMP-2) and MMP-9 were detected by ELISA. The migration and invasion abilities of HepG2 cell were determined using wound healing and Transwell invasion assays. The apoptosis of HepG2 cell induced by tanshinol was analyzed by Annexin V/propidium iodide staining. A xenograft model was constructed to investigate the inhibitory effect of tanshinol on HepG2 cell growth in vivo. To further investigate the role of tanshinol on the metastasis of HepG2 cell in vivo, an experimental metastasis assay was performed. Results:Tanshinol inhibited the growth and colony formation of HCC cell in vitro. Tanshinol also induced the apoptosis of HepG2 cell and inhibited the migration and invasion of HepG2 cell. In in vivo experiments, tanshinol suppressed the tumor growth and metastasis of HepG2 cell. Furthermore, the phosphorylation of PI3K and AKT was decreased by tanshinol in vitro and in vivo. Conclusion:Tanshinol exerts its anti-cancer effects via regulating the PI3K-AKT signaling pathway in HCC.

| S-EPMC6304085 | biostudies-other

Combination of Cordycepin and Apatinib Synergistically Inhibits NSCLC Cells by Down-Regulating VEGF/PI3K/Akt Signaling Pathway.

Project description:BackgroundThe application of apatinib is immensely limited by its acquired drug resistance. This research investigates whether cordycepin, a component from Cordyceps could synergize with apatinib to improve its anticancer effect on non-small cell lung cancer (NSCLC) cells.MethodsThe NSCLC cell lines A549, PC9, and H1993, and human bronchial epithelial (HBE) cell line Bears-2B were used in this study. Cell counting kit 8, colony formation assays, wound healing assay, transwell assay, and flow cytometry analysis were performed to assess the cell viability, the migration ability, and invasion ability of the cells. Kyoto encyclopedia of genes and genomes (KEGG), western blotting and molecular docking was applied to analyze the possible pathways affected by cordycepin.ResultsThe combination of cordycepin and apatinib in a ratio of 5:1 synergistically reduced proliferation of NSCLC cells, inhibited cell migration and invasion, increased cell apoptosis by altering cell cycle in NSCLC A549 and PC9 cells. The VEGF/PI3K/Akt pathway was inhibited after treatment with cordycepin and apatinib.ConclusionOur findings demonstrated that the combination of cordycepin and apatinib has synergistically anticancer effect on NSCLC cells by down-regulating VEGF/PI3K/Akt signaling pathway. This result indicated that cordycepin and apatinib could be a promising drug combination against NSCLC.

| S-EPMC7505117 | biostudies-literature

MicroRNA?126?3p suppresses HeLa cell proliferation, migration and invasion, and increases apoptosis via the PI3K/PDK1/AKT pathway.

Project description:We previously reported that relative to normal cervical mucus, microRNA 126?3p (miR?126?3p) is present in significantly greater amounts in the cervical mucus of patients with overt cervical cancer or precursor lesions. Here, we investigated the effects of enforced miR?126?3p expression in the cervical cancer cell line, HeLa, on proliferation, migration, invasion, apoptosis and protein expression. We transfected HeLa cells with miR?126?3p miRNA and found that proliferation, migration and invasion by cell counting, wound healing, cell migration and invasion assay were significantly reduced in these cells relative to those transfected with a negative control mimic. The levels of phosphoinositide 3 kinase (PI3K), phosphorylated 3?phosphoinositide?dependent protein kinase?1 (p?PDK1) and p?AKT proteins were lower in the miR?126?3p?transfected cells. Phosphorylated 70S6K (p?p70S6K), phosphorylated glycogen synthase kinase 3? (p?GSK3?), phosphorylated S6K (p?S6K), cyclin D1, phosphorylated p21?activated kinase 1 (p?PAK1), Rho associated coiled?coil containing protein kinase 1 (ROCK1), myotonic dystrophy?related CDC42?binding kinases ? (MRCK?) and phospholipase C ?1 (p?PLC?1) were also downregulated. This suggests that downstream effectors of the PI3K/PDK1/AKT pathway are targets for inhibition by miR?126?3p. In contrast, apoptotic?related proteins including the BCL?2?associated agonist of cell death (Bad), B?cell lymphoma?extra?large (Bcl?xL) and BCL?2?associated X (Bax), were all upregulated by miR?126?3p, resulting in increased caspase 3/7 activity and apoptosis. Thus, enforced expression of miR?126?3p inhibited cell migration and invasion and also induced apoptosis by regulating the PI3K/PDK1/AKT pathway in HeLa cells. Hence, high levels of miR?126?3p may inhibit cervical carcinogenesis, and targeting the PI3K/PDK1/AKT pathway via miR?126?3p could represent a new approach for treating patients with cervical cancer.

| S-EPMC7057934 | biostudies-literature

miR-125a-3p/FUT5-FUT6 axis mediates colorectal cancer cell proliferation, migration, invasion and pathological angiogenesis via PI3K-Akt pathway.

Project description:The fucosyltransferase (FUT) family produces glycans, a fundamental event in several cancers, including colorectal cancer (CRC). miR-125a-3p is a non-coding RNA that can reduce cell proliferation and migration in cancer. In this study, we explored the levels of miR-125a-3p and FUT expression in human CRC tissues and two human CRC cell lines by qPCR. The results showed that miR-125a-3p, FUT5 and FUT6 are differentially expressed in normal and tumour tissues. On the basis of our previous research, FUT can be regulated by miRNA, which influences the proliferation and invasion of breast and hepatocellular cancer cells. We hypothesised that FUT5 and FUT6 may be regulated by miR-125a-3p. Luciferase reporter analyses were applied to identify potential target genes of miR-125a-3p. A functional study showed that miR-125a-3p overexpression can inhibit the proliferation, migration, invasion and angiogenesis of CRC cells via down-regulating FUT5 and FUT6. In addition, regulating miR-125a-3p, FUT5 or FUT6 expression markedly modulated the activity of the PI3K/Akt signalling pathway, and this effect of FUT5 or FUT6 could be reversed by transfection with miR-125a-3p-mimics. Taken together, our data suggest that both FUT5 and FUT6 can promote the development of CRC via the PI3K/Akt signalling pathway, which is regulated by miR-125a-3p. miR-125a-3p may serve as a predictive biomarker and a potential therapeutic target in CRC treatment.

| S-EPMC5596543 | biostudies-literature

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