scholarly journals ID2 Inhibits Lung Adenocarcinoma Cell Malignant Behaviors Through Inhibiting the Activation of the PI3K/AKT/mTOR Signaling Pathway

Author(s):  
Wenzhong Peng ◽  
Jia Chen ◽  
Ruoxi He ◽  
Yongjun Tang ◽  
Juan Jiang ◽  
...  

Abstract Background: Lung cancer is the most common cancer and one of the main causes of cancer-related deaths, and it manifests as metastatic disease in most cases. Considering frequent gene mutation and/or signaling deregulation in lung adenocarcinoma, identifying novel factors or agents targeting these signaling pathways might be promising strategies for lung adenocarcinoma therapy. Methods: GEO datasets were analyzed to identify differentially expressed genes (DEGs) in lung adenocarcinoma. The specific effects of candidate gene overexpression or knockdown on lung adenocarcinoma cell phenotypes were examined. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) are used to connect the genomic and functional information of DEGs. The dynamic effects of candidate gene and signaling pathway agonist on lung adenocarcinoma malignant behaviors were investigated. Finally, clinical lung adenocarcinoma and adjacent non-cancerous tissues were collected and the levels of candidate gene were examined in tissue samples.Results: Inhibitor of DNA binding 2 (ID2) was identified as an aberrantly downregulated gene in lung adenocarcinoma. ID2 overexpression suppressed lung adenocarcinoma cell viability, colony formation capacity, and migration. ID2 overexpression also reduced the protein levels of N-cadherin, MMP2, MMP9, and the phosphorylation of AKT and mTOR. The PI3K/AKT/mTOR signaling agonist exerted opposite effects on lung adenocarcinoma cells to those of ID2 overexpression, and partially reversed the effects of ID2 overexpression. In tissue samples, ID2 protein levels and mRNA expression were also downregulated compared with those in adjacent non-cancerous tissues. Conclusion: ID2 exerts its tumor-suppressive effects on lung adenocarcinoma cell malignant behaviors through inhibiting the activation of the PI3K/AKT/mTOR signaling pathway. Restoring ID2 expression in lung adenocarcinoma cells might improve the curative effect of lung adenocarcinoma therapies.

2020 ◽  
Author(s):  
Shao-Hui Yan ◽  
Shu-Feng Xu ◽  
Lei Zheng ◽  
Li-Ying Kang ◽  
Jun-Li Cao ◽  
...  

Abstract Background The study aimed to investigate the effect and mechanism of miR-186, which targets protein tyrosine phosphatase (Shp2) PI3K/Akt/mTOR signaling pathway, on the biological characteristics of lung adenocarcinoma cells. Methods In this experimental study, Human lung adenocarcinoma cell line SPC-A-1 was grouped as Blank group, negative control (NC) group, miR-186 mimic group, miR-186 inhibitor group, si-Shp2 group and miR-186 inhibitor+si-Shp2 group. Results The results showed that miR-186 can target and down-regulate the expression of Shp2 gene. Compared with the Blank group, levels of Shp2, N-cadherin and Bcl-2 and level of PI3K/p-PI3K, Akt/P-Akt, mTOR/p-mTOR as well as cell proliferation, migration and invasion ability and the proportion of cells in S phase significantly decreased in the miR-186 mimic group and the si-Shp2 group, while the levels of E-cadherin and Bax as well as the proportion of cells in G1 phase and cell gene and mediates apoptosis rate increased significantly (all P < 0.05). Compared with the miR-186 inhibitor group, the miR-186 inhibitor + si-Shp2 group showed similar trend in all parameters with the comparison above (all P < 0.05). Conclusions The overexpression of miR-186 can down-regulate Shp2 gene expression, further inhibit the proliferation, invasion and migration and promote apoptosis of lung adenocarcinoma cells by inhibiting the activation of PI3K/Akt/mTOR signaling pathway.


2015 ◽  
Vol 309 (3) ◽  
pp. E302-E310 ◽  
Author(s):  
Caixia Li ◽  
Helmy M. Siragy

High glucose reduces autophagy and enhances apoptosis of podocytes. Previously, we reported that high glucose induced podocyte injury through upregulation of the (pro)renin receptor (PRR). We hypothesized that increasing PRR reduces autophagy and increases apoptosis of mouse podocytes exposed to high glucose via activation of the PI3K/Akt/mTOR signaling pathway. Mouse podocytes were cultured in normal (5 mmol/l) or high (25 mmol/l) d-glucose for 48 h. High glucose significantly increased mRNA and protein levels of PRR, phosphorylation of PI3K/Akt/mTOR, and p62. In contrast, high glucose decreased activation of UNC-51-like kinase-1 (ULK1) by phosphorylating Ser757 and protein levels of microtubule-associated protein-1 light chain 3B (LC3B)-II and Lamp-2. Bafilomycin A1 increased LC3BII and p62 accumulation in high-glucose-treated cells. High glucose reduced the autophagic flux. Confocal microscopy studies showed significant reduction in the protein level of LC3B in response to high glucose. Cyto-ID autophagy staining showed a significant decrease in autophagosome formation with high glucose. In the absence of PRR, activation of Akt with sc-79 or mTOR with MHY-1485 increased p62 accumulation. Caspase-3/7 activity and apoptosis monitored by TUNEL assay were significantly increased in podocytes treated with high glucose. PRR siRNA significantly reversed the effects of high glucose. Based on these data, we conclude that high glucose decreases autophagy and increases apoptosis in mouse podocytes through the PRR/PI3K/Akt/mTOR signaling pathway.


2020 ◽  
Author(s):  
Shoukai Zong ◽  
Wei Dai ◽  
Wencheng Fang ◽  
Xiangting Guo ◽  
Kai Wang

Abstract Objective This study aimed to investigate the effect of SIK2 on cisplatin resistance induced by aerobic glycolysis in breast cancer cells and its potential mechanism. Methods qRT-PCR and Western blot were used to detect SIK2 mRNA and protein levels. Cisplatin (DDP) resistant cell lines of breast cancer cells were established, CCK-8 was used to measure and evaluate the viability, and Transwell was used to evaluate the cell invasion capability. Flow cytometry was adopted to evaluate the apoptosis rate. The glycolysis level was evaluated by measuring glucose consumption and lactic acid production. The protein levels of p-PI3K, p- protein kinase B (Akt) and p-mTOR were determined by western blot. Results SIK2 is highly expressed in breast cancer tissues and cells compared with adjacent tissues and normal human breast epithelial cells, and has higher diagnostic value for breast cancer. Silencing SIK2 expression can inhibit proliferation and invasion of breast cancer cells and induce their apoptosis. In addition, SIK2 knockdown inhibits glycolysis, reverses the resistance of drug-resistant cells to cisplatin, and inhibits PI3K/AKT/mTOR signaling pathway. When LY294002 is used to inhibit PI3K/AKT/mTOR signaling pathway, the effect of Sh-SIK2 on aerobic glycolysis of breast cancer cells can be reversed. Conclusion SIK2 can promote cisplatin resistance caused by aerobic glycolysis of breast cancer cells through PI3K/AKT/mTOR signaling pathway, which may be a new target to improve cisplatin resistance of breast cancer cells.


Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1257 ◽  
Author(s):  
Inoue ◽  
Miki ◽  
Saito ◽  
Hata ◽  
Abe ◽  
...  

Cancer-associated fibroblasts (CAFs) exert various effects upon biological behaviours of cancer. In this study, we examined the correlation of CAFs with the intra-tumoural immune system in the lung adenocarcinoma microenvironment. We studied 27 and 113 cases of lung adenocarcinoma tentatively as Cohorts 1 and 2, respectively. The patients in Cohort 1 received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for recurrent lung adenocarcinoma. -smooth muscle actin (-SMA), a surrogate marker for CAFs, was examined by immunohistochemistry. We then examined the effects of CAFs isolated from lung cancer tissues on programmed death ligand 1 (PD-L1) expression in lung adenocarcinoma cell lines. No significant associations were detected between -SMA status and the ratios of CD8/CD4 and Foxp3/CD8 in Cohort 1. However, -SMA status was significantly associated with PD-L1 status in both Cohorts 1 and 2. Conditioned medium of CAFs significantly induced PD-L1 expression in lung adenocarcinoma cell lines, A549, PC-9, and H1975. Among the cytokines examined by antibody array, C-X-C motif chemokine ligand 2 (CXCL2) increased PD-L1 mRNA expression in these cell lines. CXCL2 is therefore considered to have a potential to induce PD-L1 expression in lung adenocarcinoma cells as a result of an interaction between carcinoma cells and CAFs. These findings did firstly demonstrate that CAFs indirectly influenced tumour immunity through increasing PD-L1 expression in lung adenocarcinoma cells.


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