Chaihu Guizhi Ganjiang Decoction Ameliorates Pancreatic Fibrosis via JNK/mTOR Signaling Pathway

Pancreatic fibrosis is a pathological characteristic of chronic pancreatitis (CP) and pancreatic cancer. Chaihu Guizhi Ganjiang Decoction (CGGD) is a traditional Chinese medicine, which is widely used in the clinical treatment of digestive diseases. However, the potential anti-fibrosis mechanism of CGGD in treating CP remains unclear. Here, we conducted a series of experiments to examine the effect of CGGD on the CP rat model and primary isolated pancreatic stellate cells (PSCs). The results revealed that CGGD attenuated pancreatic damage, decreased collagen deposition, and inhibited PSC activation in the pancreas of CP rats. However, compared with the CP group, CGGD had no effect on body weight and serum amylase and lipase. In addition, CGGD suppressed autophagy by downregulating Atg5, Beclin-1, and LC3B and facilitated phosphorylation of mTOR and JNK in pancreatic tissues and PSCs. Moreover, the CGGD-containing serum also decreased LC3B or collagen I expression after rapamycin (mTOR inhibitor) or SP600125 (JNK inhibitor) treatment in PSCs. In conclusion, CGGD attenuated pancreatic fibrosis and PSC activation, possibly by suppressing autophagy of PSCs through the JNK/mTOR signaling pathway.

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EPHA2 Promotes the Invasion and Migration of Human Tongue Squamous Cell Carcinoma Cal-27 Cells by Enhancing AKT/mTOR Signaling Pathway

BioMed Research International ◽

10.1155/2021/4219690 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Fengqin Wang ◽

Hanzhong Zhang ◽

Zhigang Cheng

Keyword(s):

Cell Cycle ◽

Signaling Pathway ◽

Mtor Inhibitor ◽

Mtor Signaling ◽

Biological Behavior ◽

Migration And Invasion ◽

Mtor Signaling Pathway ◽

Akt Inhibitor ◽

Invasion And Migration ◽

And Migration

EPHA2 is a member of the ephrin receptor tyrosine kinase family and is closely related to the malignant tumor progression. The effect of EPHA2 on OSCC is not clear. This study explored the role of EPHA2 and AKT/mTOR signaling pathways in Cal-27 cell invasion and migration. The expression of EPHA2 and EPHA4 in human OSCC and normal oral tissue was detected by immunohistochemistry. EPHA2-overexpressing and EPHA2-knockdown Cal-27 cells were established, and the cells were treated with an AKT inhibitor (MK2206) and mTOR inhibitor (RAD001). The expression of EPHA2 was detected by qRT-PCR, cell proliferation was evaluated by MTT assay, cell migration and invasion were examined by scratch and Transwell assay, and cell morphology and apoptosis were assessed by Hoechst 33258 staining. Western blot was performed to detect the expression of proteins related to AKT/mTOR signaling, cell cycle, and pseudopod invasion. EPHA2 and EPHA4 were highly expressed in clinical human OSCC. Overexpression of EPHA2 promoted the proliferation, migration, and invasion of Cal-27 cells, inhibited cell cycle blockage and apoptosis, and enhanced the activity of the AKT/mTOR signaling pathway. MK2206 (AKT inhibitor) and RAD001 (mTOR inhibitor) reversed the effect of EPHA2 overexpression on the biological behavior of Cal-27 cells. EPHA2 promotes the invasion and migration of Cal-27 human OSCC cells by enhancing the AKT/mTOR signaling pathway.

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Tu1367 - Lipoic Acid Inhibits the Activation of Pancreatic Stellate Cells by Pi3K/Akt/Mtor Signaling Pathway

Gastroenterology ◽

10.1016/s0016-5085(18)33183-4 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-945

Author(s):

Ran Xue ◽

Jianyu Hao

Keyword(s):

Signaling Pathway ◽

Lipoic Acid ◽

Stellate Cells ◽

Mtor Signaling ◽

Pancreatic Stellate Cells ◽

Mtor Signaling Pathway

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Total saponins of Bolbostemma paniculatum (maxim.) Franquet exert antitumor activity against MDA-MB-231 human breast cancer cells via inhibiting PI3K/Akt/mTOR pathway

BMC Complementary and Alternative Medicine ◽

10.1186/s12906-019-2708-0 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Jian-Wei Dou ◽

Rong-Guo Shang ◽

Xiao-Qin Lei ◽

Kang-Le Li ◽

Zhan-Zi Guo ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Mtor Inhibitor ◽

Therapeutic Potential ◽

Underlying Mechanism ◽

Mtor Pathway ◽

Mtor Signaling ◽

Pi3k Inhibitor ◽

Mtor Signaling Pathway ◽

And Migration

Abstract Background The aim of the present study was to examine the effects of the Bolbostemma paniculatum (Maxim.) Franquet (BP) active compound, BP total saponins (BPTS), on MDA-MB-231 cells, and investigate the underlying mechanism regarding BPTS-mediated attenuation of the PI3K/Akt/mTOR pathway. Methods The effect of BPTS on cytotoxicity, induction of apoptosis and migration on MDA-MB-231 cells at three different concentrations was investigated. A CCK-8 assay, wound-healing assay and flow cytometry were used to demonstrate the effects of BPTS. Additionally, expression of the primary members of the PI3K/Akt/mTOR signaling pathway was assessed using western blotting. To verify the underlying mechanisms, a PI3K inhibitor and an mTOR inhibitor were used. Results BPTS inhibited proliferation of MDA-MB-231 cells with an IC50 value of 10 μg/mL at 48 h. BPTS inhibited migration of MDA-MB-231 cells, and the western blot results demonstrated that BPTS reduced p-PI3K, p-Akt and p-mTOR protein expression levels in MDA-MB-231 cells. Additionally, the results were confirmed using a PI3K inhibitor and an mTOR inhibitor. BPTS decreased proliferation and migration of MDA-MB-231 cells possibly through inhibiting the PI3K/Akt/mTOR signaling pathway. Conclusions The results highlight the therapeutic potential of BPTS for treating patients with triple-negative breast cancer.

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Cezanne enhances epithelial mesenchymal transition and prevents anthracycline-induced apoptosis via AKT/mTOR signaling in hepatocellular carcinoma

10.21203/rs.3.rs-676858/v1 ◽

2021 ◽

Author(s):

Xiao-Ping Zhong ◽

Jiahong Wang ◽

Jie Mei ◽

Lianghe Lu ◽

Yihong Ling ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Cell Lines ◽

Mtor Inhibitor ◽

Epithelial Mesenchymal Transition ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Mesenchymal Transition

Abstract Background Anthracycline resistance have hindered the efficacy of transcatheter arterial chemoembolization (TACE). Translational research is therefore in need to find potential combinations by studying the resistance mechanism of anthracycline. In our published work, we found Cezanne could predict the efficacy of adjuvant TACE (ad-TACE) and induce epithelium mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). We hereby conduct a sequential investigation to reveal the role of Cezanne on EMT and its potential to retard resistance. Methods The response of Cezanne in patients treated with adjuvant TACE after hepatectomy was evaluated. Functional assays were used to examine the resistance function of Cezanne to anthracyclin. In-situ tumorigenesis models and intraperitoneal perfusion chemotherapy experiment were used for in vivo verification. Results High expression of Cezanne correlated to a better outcome. Multivariate analysis showed low expression of Cezanne and the application of postoperative ad-TACE therapy were independent prognostic risk factors. However, patient outcome was significantly shorter in high Cezanne group of ad-TACE patients. In vitro assays revealed that HCC functions were inhibited after overexpressing Cezanne (OE-Cezanne). After treated with epirubicin, however, OE-Cezanne cell lines did not respond to treatment. In vivo experiment was consistent with in vitro assays. Besides, high Cezanne transforms cell morphology and is correlated to the activation of EMT related genes. Gene set analysis showed that Cezanne can regulate PI3K/AKT/mTOR signaling pathway. Therefore, mTOR inhibitor Rapamycin can reverse the resisting effect of Cezanne on HCC cell lines. Conclusions Adjuvant anthracycline-based TACE treatment after curative surgery can reduce the recurrence rate in HCC patients. However, in patients with high Cezanne expression, the efficacy of TACE may be undermined by EMT inducement. We discovered Cezanne modulates EMT by activating the AKT/mTOR signaling pathway and provided evidence for the rationale of combining mTOR inhibitor with TACE to prevent recurrence in HCC patients.

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Coenzyme Q10 Ameliorates Pancreatic Fibrosis via the ROS-Triggered mTOR Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/8039694 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Ran Xue ◽

Jianxin Wang ◽

Lixin Yang ◽

Xinjuan Liu ◽

Yan Gao ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Coenzyme Q10 ◽

Mtor Signaling ◽

Pancreatic Fibrosis ◽

Collagen Deposition ◽

Mtor Signaling Pathway ◽

Histological Changes ◽

Expression Levels ◽

Specific Inhibitors

Aim. Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis. Any remedies that inhibit the activation of PSCs can be potential candidates for therapeutic strategies in pancreatic fibrosis-related pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). Our study is aimed at exploring the protective effect of coenzyme Q10 (CoQ10) against pancreatic fibrosis. Methods. Pancreatic fibrosis was induced by 20% L-arginine (250 mg/100 g) at 1 h intervals twice per week for 8 weeks in C57BL/6 mice. CoQ10 was administered for 4 weeks. Isolated primary PSCs from C57BL/6 mice were treated with 100 μM CoQ10 for 72 h, as well as Rosup and specific inhibitors. The effects of CoQ10 on the activation of PSCs, autophagy, collagen deposition, histological changes, and oxidative stress were analyzed by western blotting, biochemical estimations, immunofluorescence staining, and hematoxylin-eosin, Masson, and Sirius red staining, as well as with a reactive oxygen species (ROS) assay. Results. Pretreatment and posttreatment of CoQ10 decreased autophagy, activation of PSCs, oxidative stress, histological changes, and collagen deposition in the CP mouse model. In primary PSCs, expression levels of p-PI3K, p-AKT, and p-mTOR were upregulated with CoQ10. A rescue experiment using specific inhibitors of the PI3K-AKT-mTOR pathway demonstrated that the PI3K-AKT-mTOR signaling pathway was the underlying mechanism by which CoQ10 ameliorated fibrosis. With the addition of Rosup, expression levels of the autophagy biomarkers LC3 and Atg5 were elevated. Meanwhile, the levels of p-PI3K, p-AKT, and p-mTOR were lower. Conclusions. Our findings demonstrated that CoQ10 alleviates pancreatic fibrosis by the ROS-triggered PI3K/AKT/mTOR signaling pathway. CoQ10 may be a therapeutic candidate for antifibrotic methods.

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598 POSTER Analysis of the mTOR signaling pathway versus proliferative response of tumor cells to the mTOR inhibitor RAD001 (everolimus)

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(06)70603-6 ◽

2006 ◽

Vol 4 (12) ◽

pp. 181

Author(s):

M. Breuleux ◽

S. Zumstein-Mecker ◽

T. O'Reilly ◽

F. Natt ◽

M. Maira ◽

...

Keyword(s):

Signaling Pathway ◽

Tumor Cells ◽

Proliferative Response ◽

Mtor Inhibitor ◽

Mtor Signaling ◽

Mtor Signaling Pathway

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Coenzyme Q10 inhibits the activation of pancreatic stellate cells through PI3K/AKT/mTOR signaling pathway

Oncotarget ◽

10.18632/oncotarget.21247 ◽

2017 ◽

Vol 8 (54) ◽

pp. 92300-92311 ◽

Cited By ~ 18

Author(s):

Ran Xue ◽

Jing Yang ◽

Jing Wu ◽

Qinghua Meng ◽

Jianyu Hao

Keyword(s):

Signaling Pathway ◽

Coenzyme Q10 ◽

Stellate Cells ◽

Mtor Signaling ◽

Pancreatic Stellate Cells ◽

Mtor Signaling Pathway

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Glucagon-like peptide-2-stimulated protein synthesis through the PI 3-kinase-dependent Akt-mTOR signaling pathway

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00620.2010 ◽

2011 ◽

Vol 300 (3) ◽

pp. E554-E563 ◽

Cited By ~ 17

Author(s):

Xuemei Shi ◽

Xiaojie Li ◽

Yi Wang ◽

Keying Zhang ◽

Fuguo Zhou ◽

...

Keyword(s):

Protein Synthesis ◽

Signaling Pathway ◽

Hippocampal Neurons ◽

Mtor Inhibitor ◽

Kinase Inhibitor ◽

Long Term Potentiation ◽

Mtor Signaling ◽

Mucosal Cell ◽

Mtor Signaling Pathway ◽

Glucagon Like Peptide

Glucagon-like peptide-2 (GLP-2) is a nutrient-responsive neuropeptide that exerts diverse actions in the gastrointestinal tract, including enhancing mucosal cell survival and proliferation. GLP-2 stimulates mucosal growth in vivo with an increased rate of protein synthesis. However, it was unclear whether GLP-2 can directly stimulate protein synthesis. The objective was to test critically whether GLP-2 receptor (GLP-2R) activation directly stimulates protein synthesis through a PI 3-kinase-dependent Akt-mTOR signaling pathway. HEK 293 cells (transfected with human GLP-2R cDNA) were treated with human GLP-2 with/without pretreatment of PI 3-kinase inhibitor (LY-294002) or mTOR inhibitor (rapamycin). Results show that 1) GLP-2 specifically bound to GLP-2R overexpressed in the HEK cells with Ka = 0.22 nM and Bmax = 321 fmol/μg protein; 2) GLP-2-stimulated protein synthesis was dependent on the amount of GLP-2R cDNA and the dosage of GLP-2 and reached the plateau among 0.2–2 nM GLP-2; 3) GLP-2-stimulated protein synthesis was abolished by the PI 3-kinase inhibitor and mTOR inhibitor; and 4) GLP-2-mediated stimulation of phosphorylation on Akt and mTOR was dependent on the amount of GLP-2R cDNA transfected and the dosage of GLP-2. In addition, GLP-2-mediated action and signaling in regulation of protein synthesis were confirmed in mouse hippocampal neurons (expressing native GLP-2R). GLP-2 directly stimulated protein synthesis of primary cultured neurons in dosage-dependent, PI 3-kinase-dependent, and rapamycin-sensitive manners, which linked with activation of Akt-mTOR signaling pathway as well. We conclude that GLP-2R activation directly stimulates protein synthesis by activating the PI 3-kinase-dependent Akt-mTOR signaling pathway. GLP-2-stimulated protein synthesis may be physiologically relevant to maintaining neuronal long-term potentiation and providing secondary mediators (namely neuropeptides or growth factors).

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