scholarly journals Krüppel-like factor 8 promotes aerobic glycolysis in prostate cancer cells by regulating AKT/mTOR signaling pathway

2020 ◽  
Vol 19 (10) ◽  
pp. 2091-2096
Author(s):  
Cunming Zhang ◽  
Song Chen ◽  
Lide Song ◽  
Haibo Ye ◽  
Junwei Wang
Keyword(s):  
Prostate Cancer ◽  
Cell Viability ◽  
Signaling Pathway ◽  
Therapeutic Target ◽  
Aerobic Glycolysis ◽  
Lactic Acid Production ◽  
Mtor Signaling ◽  
Cell Counting ◽  
Mtor Signaling Pathway

Purpose: To investigate the effects of Krüppel-like factor 8 (KLF8) in prostate cancer (PCa) cell viability and glycolysis, and explore its role as a regulatory factor.Methods: Immunoblot assays were conducted to assess the expression of KLF8 and proteins in AKT/mTOR pathway in PCa cell lines PC-3 and DU145. Cell Counting Kit-8 assays were performed to assess the effect of KLF8 on PCa cell viability. The glycolysis capacity of PCa cells was determined by measuring the levels of glucose intake, lactic acid production, and cellular ATP levels.Results: Depletion of KLF8 decreased the survival of PCa cells in vitro (p < 0.05). KLF8 depletion also inhibited aerobic glucose metabolism in PCa cells (p < 0.05). Further studies confirmed that KLF8 contributed to the growth and glycolysis of PCa cells via the regulation of AKT/mTOR pathway.Conclusion: KLF8 regulates glycolysis in PCa cells by regulating AKT/mTOR signaling pathway and is thus a promising therapeutic target for PCa treatment. Keywords: Krüppel-like factor 8 (KLF8), Prostate cancer (PCa), Aerobic glucose, AKT/mTOR signaling pathway, Therapeutic target

scholarly journals Inhibition of Prostate Cancer DU-145 Cells Proliferation by Anthopleura anjunae Oligopeptide (YVPGP) via PI3K/AKT/mTOR Signaling Pathway

Marine Drugs ◽  
2018 ◽  
Vol 16 (9) ◽  
pp. 325 ◽  
Author(s):  
Xiaojuan Li ◽  
Yunping Tang ◽  
Fangmiao Yu ◽  
Yu Sun ◽  
Fangfang Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Nude Mouse Model ◽  
Dose Dependent

We investigated the antitumor mechanism of Anthopleura anjunae oligopeptide (AAP-H, YVPGP) in prostate cancer DU-145 cells in vitro and in vivo. Results indicated that AAP-H was nontoxic and exhibited antitumor activities. Cell cycle analysis indicated that AAP-H may arrest DU-145 cells in the S phase. The role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/AKT/mTOR) signaling pathway in the antitumor mechanism of APP-H was investigated. Results showed that AAP-H treatment led to dose-dependent reduction in the levels of p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448), whereas t-AKT and t-PI3K levels remained unaltered compared to the untreated DU-145 cells. Inhibition of PI3K/AKT/mTOR signaling pathway in the DU-145 cells by employing inhibitor LY294002 (10 μM) or rapamycin (20 nM) effectively attenuated AAP-H-induced phosphorylation of AKT and mTOR. At the same time, inhibitor addition further elevated AAP-H-induced cleaved-caspase-3 levels. Furthermore, the effect of AAP-H on tumor growth and the role of the PI3K/AKT/mTOR signaling pathway in nude mouse model were also investigated. Immunohistochemical analysis showed that activated AKT, PI3K, and mTOR levels were reduced in DU-145 xenografts. Western blotting showed that AAP-H treatment resulted in dose-dependent reduction in p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448) levels, whereas t-AKT and t-PI3K levels remained unaltered. Similarly, Bcl-xL levels decreased, whereas that of Bax increased after AAP-H treatment. AAP-H also increased initiator (caspase 8 and 9) and executor caspase (caspase 3 and 7) levels. Therefore, the antitumor mechanism of APP-H on DU-145 cells may involve regulation of the PI3K/AKT/mTOR signaling pathway, which eventually promotes apoptosis via mitochondrial and death receptor pathways. Thus, the hydrophobic oligopeptide (YVPGP) can be developed as an adjuvant for the prevention or treatment of prostate cancer in the future.

scholarly journals Endothelial Cells Promote Docetaxel Resistance of Prostate Cancer via FGF2/ERG/Akt/mTOR Signaling Pathway

2020 ◽  
Author(s):  
Wen-Hao Zhou ◽  
Yi-Ming Su ◽  
Yu Zhang ◽  
Bang-Min Han ◽  
Hai-Tao Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Endothelial Cells ◽  
Cell Line ◽  
Signaling Pathway ◽  
Umbilical Vein ◽  
Mtor Signaling ◽  
Castration Resistant Prostate Cancer ◽  
Mtor Signaling Pathway ◽  
Docetaxel Resistance

Abstract Background Docetaxel is a first-line chemotherapy for the treatment of patients with castration-resistant prostate cancer (CRPC). Despite the good initial response of docetaxel, drug resistance will inevitably occur. Mechanisms underlying docetaxel resistance are not well elaborated. Endothelial cells (ECs) have been implicated in the progression and metastasis of prostate cancer (PCa). However, little attention has been paid to the role of ECs in the development of docetaxel resistance in PCa. Methods Here, we sought to investigate the function and mechanism of ECs involving in the docetaxel resistance of PCa. The 22Rv1 and C4-2B PCa cell lines were cultured with or without human umbilical vein endothelial cells (HUVEC). The proliferation of each PCa cell line was assessed by CCK8 and EdU assays. Cell viability of each PCa cell line treated with docetaxel was evaluated by CCK8. Apoptosis was measured by flow cytometry. Quantitative reverse transcription (RT)-PCR assay was used to determine the expression of ETS related gene (ERG) in each PCa cell line and FGF2 in HUVEC. The proteins including ERG, Caspase3, PARP, Akt, p-Akt, mTOR and p-mTOR were quantified by western blotting. ERG overexpressing C4-2B cells(C4-2B-ERG) were constructed by transfection with pLenti6.3-ERG lentivirus. C4-2B-ERG cells were knocked down by transfecting with ERG siRNAs. Differentially expressed cytokines between the serum-free media from 22Rv1 and 22Rv1/HUVEC co-culture system were detected by human cytokine array and determined by ELISA assay. Tumors were induced in mice by injecting 22Rv1 cells with or without HUVEC and treated with docetaxel. Tumor growth and apoptosis were examined by immunohistochemistry and TUNEL respectively. Results ECs promoted proliferation and inhibited apoptosis in PCa cells (in vitro) and mouse xenograft tumors induced by these cells (in vivo) under docetaxel treatment. ECs secreted FGF2 to induce ERG expression and activate the Akt/mTOR signaling pathway in PCa cells contributing to docetaxel resistance. Blocking FGF2 could reverse the enhancing effects of HUVEC on docetaxel resistance in PCa cells. Inhibition of the Akt/mTOR signaling pathway could alleviate chemoresistance mediated by ERG. Conclusion ECs promote docetaxel resistance via FGF2/ERG/Akt/mTOR signaling pathway in PCa cells. Targeting FGF/ FGFR signaling may represent a promising therapeutic strategy to overcome docetaxel resistance.

scholarly journals Rapamycin Antagonizes BCRP-Mediated Drug Resistance Through the PI3K/Akt/mTOR Signaling Pathway in mPRα-Positive Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing Zhang ◽  
Jing Hu ◽  
Weiwei Li ◽  
Chunyan Zhang ◽  
Peng Su ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Therapeutic Option ◽  
Poor Response ◽  
Mtor Signaling ◽  
Cell Counting ◽  
Mtor Signaling Pathway ◽  
Potential Biomarker ◽  
Response To Chemotherapy

PurposeOverexpression of breast cancer (BCa) resistance protein (BCRP) is detected in approximately 30% of BCa cases. BCRP indicates a poor response to chemotherapy, and it has become a classic target to overcome drug-resistant tumor cells. In this study, we aimed to explore the mechanism of BCRP overexpression and a strategy to reverse this overexpression in invasive BCa.MethodsBCRP expression in BCa tissues was determined by immunohistochemistry. GSE25066 was downloaded from the NCBI GEO database. Western blot was used to determine the expression of key molecules in vitro. Cell counting kit-8 assays were used to assess the drug response of BCa cells.ResultsOur results suggested that BCRP is an independent risk factor for BCa. We further established that upon 17α-PG binding, membrane progesterone receptor α (mPRα) promoted BCRP expression via the PI3K/Akt/mTOR signaling pathway. mPRα physically interacted with p-Akt1 S473. Moreover, rapamycin, an inhibitor of mTOR complex 1 (mTORC1), downregulated BCRP expression and enhanced the effects of particular drugs, including doxorubicin and paclitaxel.ConclusionBCRP is a potential biomarker of poor prognosis in BCa. BCRP expression is regulated by 17α-PG in mPRα-positive BCa cells through the PI3K/Akt/mTOR signaling pathway. Rapamycin might enhance the therapeutic effect of chemotherapy agents in mPRα-positive MDA-MB-453/BCRP cells and might be a therapeutic option for mPRα-positive invasive BCa with BCRP overexpression.

scholarly journals Kinesin family member 18B regulates the proliferation and invasion of human prostate cancer cells

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Yu-Peng Wu ◽  
Zhi-Bin Ke ◽  
Wen-Cai Zheng ◽  
Ye-Hui Chen ◽  
Jun-Ming Zhu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Family Member ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Mouse Xenograft Model ◽  
Kinesin Family

AbstractExpression of kinesin family member 18B (KIF18B), an ATPase with key roles in cell division, is deregulated in many cancers, but its involvement in prostate cancer (PCa) is unclear. Here, we investigated the expression and function of KIF18B in human PCa specimens and cell lines using bioinformatics analyses, immunohistochemical and immunofluorescence microscopy, and RT-qPCR and western blot analyses. KIF18B was overexpressed in PCa specimens compared with paracancerous tissues and was associated with poorer disease-free survival. In vitro, KIF18B knockdown in PCa cell lines promoted cell proliferation, migration, and invasion, and inhibited cell apoptosis, while KIF18B overexpression had the opposite effects. In a mouse xenograft model, KIF18B overexpression accelerated and promoted the growth of PCa tumors. Bioinformatics analysis of control and KIF18B-overexpressing PCa cells showed that genes involved in the PI3K–AKT–mTOR signaling pathway were significantly enriched among the differentially expressed genes. Consistent with this observation, we found that KIF18B overexpression activates the PI3K–AKT–mTOR signaling pathway in PCa cells both in vitro and in vivo. Collectively, our results suggest that KIF18B plays a crucial role in PCa via activation of the PI3K–AKT–mTOR signaling pathway, and raise the possibility that KIF18B could have utility as a novel biomarker for PCa.

Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases

2020 ◽  
Vol 27 ◽  
Author(s):  
Naser-Aldin Lashgari ◽  
Nazanin Momeni Roudsari ◽  
Saeideh Momtaz ◽  
Negar Ghanaatian ◽  
Parichehr Kohansal ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Cochrane Library ◽  
Mtor Signaling Pathway ◽  
Inflammatory Bowel

: Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview on plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

scholarly journals Upregulation of Long Noncoding RNA_GAS5 Suppresses Cell Proliferation and Metastasis in Laryngeal Cancer via Regulating PI3K/AKT/mTOR Signaling Pathway

2021 ◽  
Vol 20 ◽  
pp. 153303382199007
Author(s):  
Wenlin Liu ◽  
Jiandong Zhan ◽  
Rong Zhong ◽  
Rui Li ◽  
Xiaoli Sheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Laryngeal Cancer ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Proliferation And Metastasis ◽  
Cancer Tissues ◽  
Lncrna Gas5

Background: Laryngeal cancer is one of the most common malignant tumors among head and neck cancers. Accumulating studies have indicated that long noncoding RNAs (lncRNAs) play an important role in laryngeal cancer occurrence and progression, however, the functional roles and relative regulatory mechanisms of lncRNA growth arrest-specific transcript 5 (GAS5) in laryngeal cancer progression remain unclear. Methods: The expression of lncRNA GAS5 in both laryngeal cancer tissues and cell lines was evaluated using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay. The relationships between lncRNA GAS5 expression and clinical parameters were also analyzed. To determine the biological function of lncRNA GAS5, a lncRNA GAS5-specific plasmid was first transfected into laryngeal cancer cells using lentiviral technology. Cell counting kit-8 assay, flow cytometry, and Transwell assays were used to detect in vitro cell proliferation, apoptosis, cycle distribution, and metastasis abilities, respectively. Furthermore, in vivo cell growth experiments were also performed using nude mice. Additionally, western blotting was performed to identify the underlying regulatory mechanism. Results: In the current study, lncRNA GAS5 was downregulated in laryngeal cancer tissues and its low expression was closely associated with poor tumor differentiation, advanced TNM stage, lymph node metastasis, and shorter overall survival time. In addition, lncRNA GAS5 upregulation significantly inhibited laryngeal cancer cell proliferation both in vitro and in vivo. Moreover, in response to lncRNA GAS5 overexpression, more laryngeal cancer cells were arrested at the G2/M stage, accompanied by increased cell apoptosis rates and suppressed migration and invasion capacities. Mechanistically, our data showed that the overexpression of lncRNA GAS5 significantly regulated the PI3K/AKT/mTOR signaling pathway. Conclusion: LncRNA GAS5 might act as a suppressor gene during laryngeal cancer development, as it suppressed cell proliferation and metastasis by regulating the PI3K/AKT/mTOR signaling pathway; thus, lncRNA GAS5 is a promising therapeutic biomarker for the treatment of laryngeal cancer.

MO243STUDY ON THE EFFECT AND MECHANISM OF NOVEL REGULATORY T CELL (CD4+CD126LOWFOXP3+ TREG) IMMUNOTHERAPY IN LUPUS NEPHRITIS*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Zhenjian Xu ◽  
Junzhe Chen ◽  
Anping Xu
Keyword(s):  
T Cell ◽  
Lupus Nephritis ◽  
Signaling Pathway ◽  
B Lymphocytes ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Proliferation And Differentiation ◽  
Inflammatory State

Abstract Background and Aims Our previous study found a new regulatory T cell subpopulation, CD4+CD126lowFoxp3+ regulatory T cells (CD4+CD126lowFoxp3+ Treg). This cell can maintain a stable immune regulatory function in the inflammatory state. Through in vivo and in vitro experiments, we have confirmed that CD4+CD126lowFoxp3+ Treg has an immunotherapeutic effect on T cell-mediated mouse models of autoimmune diseases such as colitis and collagen-induced arthritis (CIA). Further experimental studies showed that CD4+CD126lowFoxp3+ Treg could reduce the kidney injury caused by autoantibodies and prolong the survival time of lupus mice. However, the mechanism of CD4+CD126lowFoxp3+ Treg immunotherapy in lupus nephritis is not clear. The purpose of this study was to explore the mechanism of CD4+CD126lowFoxp3+ Treg immunotherapy in mice with lupus nephritis. Method In vitro experiments CD4+CD126lowFoxp3+ Treg or CD4+CD126lowFoxp3+ Treg pretreated with PD-1 inhibitor were co-cultured with T or B lymphocytes of lupus mice under different in vitro culture condition. The expression levels of Akt and mTOR of Treg in each group were measured under immunoinflammatory conditions. To observe the effects and differences of Treg groups on the activation, proliferation and differentiation of T or B cells and other immunomodulatory effects. In vivo experiments CD4+CD126lowFoxp3+ Treg (2 × 106/mouse) and CD4+CD126lowFoxp3+ Treg (2 × 106/mouse) pretreated with PD-1 inhibitor and PBS were injected into NZM2328 lupus mice, respectively. After cell injection, urine protein was measured weekly. Autoantibody expression in lupus mice was measured every two weeks. The effects of Treg on the proliferation and differentiation of T/B cells in lupus mice were observed. The therapeutic effects of Treg on lupus mice were observed. Results Compared with CD4+CD126lowFoxp3+ Treg, the expression of Akt and mTOR increases in PD-1 inhibitors pretreatment cells. The activation, proliferation and differentiation functions of T or B lymphocytes of lupus mice were significantly weakened by immunosuppression of PD-1 inhibitors pretreated Treg in vitro, indicating that CD4+CD126lowFoxp3+ Treg may inhibit Akt-mTOR signaling pathway through PD-1 in in vitro. Compared with CD4+CD126lowFoxp3+ Treg, the activation, proliferation and differentiation functions of T or B lymphocytes of lupus mice were significantly weakened by immunosuppression of PD-1 inhibitors pretreated Treg in vivo. And its therapeutic effect on lupus mice was ineffective, indicating that CD4+CD126lowFoxp3+ Treg may inhibit Akt-MTOR signaling pathway through PD-1 in vivo. Conclusion CD4+CD126lowFoxp3+ Treg may inhibit the Akt-mTOR signaling pathway by expressing PD-1, and maintain stable immunomodulatory function in the inflammatory state, thus producing immunotherapeutic effect on lupus nephritis mice.

SIK2 Promotes Cisplatin Resistance Induced by Aerobic Glycolysis in Breast Cancer Cells through PI3K/AKT/mTOR Signaling Pathway

2020 ◽  
Author(s):  
Shoukai Zong ◽  
Wei Dai ◽  
Wencheng Fang ◽  
Xiangting Guo ◽  
Kai Wang
Keyword(s):  
Breast Cancer ◽  
Western Blot ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Cisplatin Resistance ◽  
Aerobic Glycolysis ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Protein Levels

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.

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