Chidamide Inhibits Cell Proliferation via the PI3K/AKT Pathway in K562 Cells Based on Network Pharmacology and Experimental Validation

2021 ◽  
Vol 27 ◽  
Author(s):  
Simin Liang ◽  
Xiaojia Zhou ◽  
Duo Cai ◽  
Fernando Rodrigues-Lima ◽  
Li Wang
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
K562 Cells ◽  
Akt Signaling ◽  
Akt Pathway ◽  
Network Pharmacology ◽  
Dependent Manner ◽  
Akt Signaling Pathway ◽  
Antitumor Effects

Background: Chidamide, a novel benzamide-type histone deacetylase (HDAC) inhibitor, exerts antitumor effects on several types of cancer. However, the role of Chidamide in chronic myeloid leukemia (CML) remains elusive. Therefore, the present study aimed to investigate the effects of Chidamide on CML cell proliferation and explore its underlying mechanism. Methods: Cell proliferation was assessed by CCK-8 assay, cell cycle distribution and apoptosis were detected by flow cytometry and the expression of related proteins was evaluated by western blot analysis. The potential mechanisms were systematically explored by the network-based pharmacological methods, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Results: The results revealed that Chidamide inhibited the proliferation of K562 cells in a dose- and time-dependent manner. In addition, Chidamide blocked cells in the G0/G1 phase via downregulating cyclin‑dependent kinase 4, and induced apoptosis via upregulating Bax and downregulating of Bcl-2. Additionally, using network-based pharmacological methods, we found that PI3K/AKT signaling pathway is involved and significantly related to cell proliferation in CML. Intriguingly, cell treatment with Chidamide suppressed the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway via decreasing the levels of phosphorylated (p)-PI3K and p-AKT. Moreover, insulin-like growth factor 1 (IGF-1), a PI3K/AKT activator, reversed the inhibitory effects of Chidamide on K562 cell proliferation. Conclusion: The study demonstrated that Chidamide may inhibit the proliferation of K562 cells by promoting cell cycle arrest and apoptosis via suppressing the PI3K/AKT pathway, suggesting that Chidamide could be a promising approach to the treatment of CML.

scholarly journals Silencing of lncRNA UCA1 inhibited the pathological progression in PCOS mice through the regulation of PI3K/AKT signaling pathway

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Dongyong Yang ◽  
Yanqing Wang ◽  
Yajing Zheng ◽  
Fangfang Dai ◽  
Shiyi Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Structural Damage ◽  
Polycystic Ovary ◽  
Serum Insulin ◽  
Tumor Cell Line ◽  
Akt Signaling ◽  
Akt Signaling Pathway

Abstract Background Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among reproductive-aged women worldwide, however, the mechanisms and progression of PCOS still unclear due to its heterogeneous nature. Using the human granulosa-like tumor cell line (KGN) and PCOS mice model, we explored the function of lncRNA UCA1 in the pathological progression of PCOS. Results CCK8 assay and Flow cytometry were used to do the cell cycle, apoptosis and proliferation analysis, the results showed that UCA1 knockdown in KGN cells inhibited cell proliferation by blocking cell cycle progression and promoted cell apoptosis. In the in vivo experiment, the ovary of PCOS mice was injected with lentivirus carrying sh-UCA1, the results showed that knockdown of lncRNA UCA1 attenuated the ovary structural damage, increased the number of granular cells, inhibited serum insulin and testosterone release, and reduced the pro-inflammatory cytokine production. Western blot also revealed that UCA1 knockdown in PCOS mice repressed AKT activation, inhibitor experiment demonstrated that suppression of AKT signaling pathway, inhibited the cell proliferation and promoted apoptosis. Conclusions Our study revealed that, in vitro, UCA1 knockdown influenced the apoptosis and proliferation of KGN cells, in vivo, silencing of UCA1 regulated the ovary structural damage, serum insulin release, pro-inflammatory production, and AKT signaling pathway activation, suggesting lncRNA UCA1 plays an important role in the pathological progression of PCOS.

scholarly journals MicroRNA-561 Affects Proliferation and Cell Cycle Transition Through PTEN/AKT Signaling Pathway by Targeting P-REX2a in NSCLC

2020 ◽  
Vol 28 (2) ◽  
pp. 147-159 ◽  
Author(s):  
ZiJun Liao ◽  
Qi Zheng ◽  
Ting Wei ◽  
YanBing Zhang ◽  
JieQun Ma ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Nsclc Cell ◽  
Luciferase Reporter ◽  
Akt Signaling Pathway ◽  
Proliferation And Metastasis ◽  
Exogenous Expression ◽  
Induced Apoptosis

MicroRNAs (miRNAs) play crucial roles in tumorigenesis and tumor progression. miR-561 has been reported to be downregulated in gastric cancer and affects cancer cell proliferation and metastasis. However, the role and underlying molecular mechanism of miR-561 in human non-small cell lung cancer (NSCLC) remain unknown and need to be further elucidated. In this study, we discovered that miR-561 expression was downregulated in human NSCLC tissues and cell lines. The overexpression of miR-561 inhibited NSCLC cell proliferation and cell cycle G1/S transition and induced apoptosis. The inhibition of miR-561 facilitated cell proliferation and G1/S transition and suppressed apoptosis. miR-561 expression was inversely correlated with P-REX2a expression in NSCLC tissues. P-REX2a was confirmed to be a direct target of miR-561 using a luciferase reporter assay. The overexpression of miR-561 decreased P-REX2a expression, and the suppression of miR-561 increased P-REX2a expression. Particularly, P-REX2a silencing recapitulated the cellular and molecular effects observed upon miR-561 overexpression, and P-REX2a overexpression counteracted the effects of miR-561 overexpression on NSCLC cells. Moreover, both exogenous expression of miR-561 and silencing of P-REX2a resulted in suppression of the PTEN/AKT signaling pathway. Our study demonstrates that miR-561 inhibits NSCLC cell proliferation and G1/S transition and induces apoptosis through suppression of the PTEN/AKT signaling pathway by targeting P-REX2a. These findings indicate that miR-561 plays a significant role in NSCLC progression and serves as a potential therapeutic target for NSCLC.

scholarly journals MicroRNA-1269 promotes cell proliferation via the AKT signaling pathway by targeting RASSF9 in human gastric cancer

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Wen-Li Liu ◽  
Hu-xia Wang ◽  
Cheng-xin Shi ◽  
Fei-yu Shi ◽  
Ling-yu Zhao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Target Gene ◽  
Akt Signaling ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Akt Signaling Pathway ◽  
Qrt Pcr

Abstract Background MicroRNAs (miRNAs) play key roles in tumorigenesis and progression of gastric cancer (GC). miR-1269 has been reported to be upregulated in several cancers and plays a crucial role in carcinogenesis and cancer progression. However, the biological function of miR-1269 in human GC and its mechanism remain unclear and need to be further elucidated. Methods The expression of miR-1269 in GC tissues and cell lines was detected by quantitative real-time PCR (qRT-PCR). Target prediction programs (TargetScanHuman 7.2 and miRBase) and a dual-luciferase reporter assay were used to confirm that Ras-association domain family 9 (RASSF9) is a target gene of miR-1269. The expression of RASSF9 was measured by qRT-PCR and Western blotting in GC tissues. MTT and cell counting assays were used to explore the effect of miR-1269 on GC cell proliferation. The cell cycle and apoptosis were measured by flow cytometry. RASSF9 knockdown and overexpression were used to further verify the function of the target gene. Results We found that miR-1269 expression was upregulated in human GC tissues and cell lines. The overexpression of miR-1269 promoted GC cell proliferation and cell cycle G1-S transition and suppressed apoptosis. The inhibition of miR-1269 inhibited cell growth and G1-S transition and induced apoptosis. miR-1269 expression was inversely correlated with RASSF9 expression in GC tissues. RASSF9 was verified to be a direct target of miR-1269 by using a luciferase reporter assay. The overexpression of miR-1269 decreased RASSF9 expression at both the mRNA and protein levels, and the inhibition of miR-1269 increased RASSF9 expression. Importantly, silencing RASSF9 resulted in the same biological effects in GC cells as those induced by overexpression of miR-1269. Overexpression of RASSF9 reversed the effects of miR-1269 overexpression on GC cells. Both miR-1269 overexpression and RASSF9 silencing activated the AKT signaling pathway, which modulated cell cycle regulators (Cyclin D1 and CDK2). In contrast, inhibition of miR-1269 and RASSF9 overexpression inhibited the AKT signaling pathway. Moreover, miR-1269 and RASSF9 also regulated the Bax/Bcl-2 signaling pathway. Conclusions Our results demonstrate that miR-1269 promotes GC cell proliferation and cell cycle G1-S transition by activating the AKT signaling pathway and inhibiting cell apoptosis via regulation of the Bax/Bcl-2 signaling pathway by targeting RASSF9. Our findings indicate an oncogenic role of miR-1269 in GC pathogenesis and the potential use of miR-1269 in GC therapy.

scholarly journals miR-499 promotes immature porcine Sertoli cell growth through the PI3K/AKT pathway by targeting the PTEN gene

Reproduction ◽  
2020 ◽  
Vol 159 (2) ◽  
pp. 145-157 ◽  
Author(s):  
Hu Gao ◽  
Bin Chen ◽  
Hui Luo ◽  
Bo Weng ◽  
Xiangwei Tang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Signaling Pathway ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Akt Signaling ◽  
Akt Pathway ◽  
Pten Gene ◽  
Seminiferous Tubules ◽  
Akt Signaling Pathway

Sertoli cells are indispensable for normal spermatogenesis, and increasing evidence has shown that miRNAs participate in the regulation of Sertoli cell growth. However, the functions and regulatory mechanisms of miRNAs in Sertoli cells of domestic animals have not been fully investigated. In the present study, we mainly investigated the regulatory roles of miR-499 in immature porcine Sertoli cells. The results showed that miR-499 was mainly located in the basement section of seminiferous tubules of prepubertal porcine testicular tissue. Overexpression of miR-499 promoted cell proliferation and inhibited apoptosis, whereas miR-499 inhibition resulted in the opposite effect. The PTEN gene was directly targeted by miR-499, and the expression of mRNA and protein was also negatively regulated by miR-499 in immature porcine Sertoli cells. siRNA-induced PTEN knockdown resulted in a similar effect as an overexpression of miR-499 and abolished the effects of miR-499 inhibition on immature porcine Sertoli cells. Moreover, both miR-499 overexpression and the PTEN knockdown activated the PI3K/AKT signaling pathway, whereas inhibition of the PI3K/AKT signaling pathway caused immature porcine Sertoli cell apoptosis and inhibited cell proliferation. Overall, miR-499 promotes proliferation and inhibits apoptosis in immature porcine Sertoli cells through the PI3K/AKT pathway by targeting the PTEN gene. This study provides novel insights into the effects of miR-499 in spermatogenesis through the regulation of immature Sertoli cell proliferation and apoptosis.

scholarly journals Effects of Fibronectin 1 on Cell Proliferation, Senescence and Apoptosis of Human Glioma Cells Through the PI3K/AKT Signaling Pathway

2018 ◽  
Vol 48 (3) ◽  
pp. 1382-1396 ◽  
Author(s):  
Yu-Xiang Liao ◽  
Zhi-Ping Zhang ◽  
Jie Zhao ◽  
Jing-Ping Liu
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Enrichment Analysis ◽  
Akt Signaling ◽  
Pathway Enrichment Analysis ◽  
Akt Signaling Pathway ◽  
Go Enrichment ◽  
Go Enrichment Analysis

Background/Aims: The current study aimed to investigate the role by which fibronectin 1 (FN1) influences the cell cycle, senescence and apoptosis in human glioma cells through the PI3K/ AKT signaling pathway. Methods: Differentially expressed genes (DEGs) were identified based on gene expression data (GSE12657, GSE15824 and GSE45921 datasets) and probe annotation files from Gene Expression Omnibus. The DEGs were identified in connection with gene ontology (GO) enrichment analysis and with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The positive expression of the FN1 protein was detected by immunohistochemistry. The glioma cell lines U251 and T98G were selected and assigned into blank, negative control (NC) and siRNA-FN1 groups. A dual luciferase reporter gene assay was used to investigate the effects of FN1 on transcriptional activity through the PI3K/AKT signaling pathway. An MTT assay was applied for the detection of cell proliferation, while flow cytometry was employed for cell cycle stage and cellular apoptosis detection. β-galactosidase staining was utilized to detect cellular senescence, a scratch test was applied to evaluate cell migration, and a transwell assay was used to analyze cell invasion. Western blotting and qRT-PCR methods were used to detect the protein and mRNA expression levels, respectively, of the FN1 gene and the related genes in the PI3K/AKT pathway (PI3K, AKT and PTEN), the cell cycle (pRb, CDK4 and Cyclin D1) and cell senescence (p16 and p21) among the collected tissues and cells. Results: GSE12657 profiling revealed FN1 to be the most upregulated gene in glioma. Regarding the GSE12657 and GSE15824 datasets, FN1 gene expression was higher in glioma tissues than in normal tissues. GO enrichment analysis and KEGG pathway enrichment analysis indicated that FN1 is involved in the synthesis of extracellular matrix (ECM) components and the PI3K/AKT signaling pathway. Verification was provided, indicating the role played by the FN1 gene in the regulation of the PI3K/AKT signaling pathway, as silencing the FN1 gene was found to inhibit cell proliferation, promote cell apoptosis and senescence, and reduce migration and invasion through the down-regulation of FN1 gene expression and disruption of the PI3K-AKT signaling pathway. Conclusion: The findings of this study provide evidence highlighting the prominent role played by FN1 in stimulating glioma growth, invasion, and survival through the activation of the PI3K/AKT signaling pathway.

MicroRNA-301a Promotes Cell Proliferation and Resistance to Apoptosis through PTEN/PI3K/Akt Signaling Pathway in Human Ovarian Cancer

2021 ◽  
pp. 1-9
Author(s):  
Jie Ni ◽  
Ying Chen ◽  
Beibei Fei ◽  
Yan Zhu ◽  
Yibei Du ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Critical Role ◽  
Akt Signaling ◽  
Ovarian Cancer Cells ◽  
Control Group ◽  
Akt Signaling Pathway

Background: MicroRNAs are endogenous small noncoding RNAs, which play a critical role in regulating various biological and pathologic processes. Furthermore, miR-301a has been detected to be overly expressed in tumorigenic progression of ovarian cancer. However, the effects of miR-301a on ovarian cancer are still unclear. Objective: The objective of this study is to investigate the molecular mechanisms of miR-301a in epithelial ovarian cancer cells. Methods: The miR-301a expression in ovarian cancer cells was detected. Then, cell proliferation, cell cycle, and apoptosis of the miR-301a-mimic-transfected ovarian cancer cells were determined, as well as the effects of the miR-301a mimic on the PTEN/phosphoinositide 3-kinase (PI3K) signaling pathway were explored. Results: We found that the miR-301a expression levels were markedly upregulated in ovarian cancer tissues and cells, and upregulation of miR-301a-promoted cell viability and proliferation. Our results also showed that the miR-301a-mimic accelerated cell cycle progression of ovarian cancer cells by targeting the CDK4/Cyclin-D1 pathway but not the CDK2/Cyclin-E pathway. Moreover, transfection of the miR-301a mimic into ovarian cancer cells could decrease the PTEN expression while increasing the PI3K and Akt phosphorylation, as compared with the miR-301a inhibitor group and the negative control group. Conclusion: Therefore, miR-301a should be an oncogene in ovarian cancer, and overexpression of miR-301a promoted proliferation of ovarian cancer cells by modulating the PTEN/PI3K/Akt signaling pathway.

Eriodictyol Suppresses Survival of Cervical Cancer Cells Through Mediation of PTEN/Akt Signaling Pathway

2019 ◽  
Vol 18 (2) ◽  
pp. 196-200
Author(s):  
Yu Lixiao ◽  
Liu Xiaoyun
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Hela Cells ◽  
Akt Signaling ◽  
Dependent Manner ◽  
Akt Signaling Pathway ◽  
Cervical Cancer Cells

Cervical cancer is one of the most malignant cancers of the female reproductive system with high morbidity and mortality. In the current study, we have examined the effect of eriodictyol on cell survival including cell growth, cell cycle and apoptosis of cervical cancer cells and also explored the underlying mechanism(s). To this end, CCK-8 assay, flow cytometry and western blotting assays were performed in cervical cancer HeLa cells. Eriodictyol significantly inhibited cell survival including impeding the cell viability, arresting the cell cycle at the G1 phase and potentiating cell apoptosis in a concentration-dependent manner. Also, ERI activated PTEN, P21, cleaved caspase-3/-9 expression and downregulated P-Akt and cyclin D1 expression in a dose-dependent manner. In conclusion, ERI can inhibit cervical cancer HeLa cells viability via impeding cell cycle and inducing apoptosis by regulating PTEN/Akt signaling pathway.

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