scholarly journals Inhibition of notch1 signaling in tumor-initiating cells overcomes chemoresistance and promotes apoptosis

2021 ◽  
pp. 30-30
Author(s):  
Yang Rui ◽  
Zhan Gang ◽  
Zhou Jun ◽  
Jin Weidong ◽  
Jiang Hui
Keyword(s):  
Western Blot ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Akt Signaling ◽  
Positive Staining ◽  
Sirna Transfection ◽  
Tumor Initiating Cells ◽  
Apoptosis Resistance ◽  
Apoptotic Pathway

The Notch signaling pathway is an evolutionarily conserved pathway essential for regulation of cell development and differentiation. Upregulation and activation of Notch signaling enhances the oncogenic potential of cancer cells through apoptosis resistance. The NOTCH1 expression pattern in hepatocellular cancer (HCC) and its role in apoptosis attenuation was determined. Immunohistostaining identified intensive positive staining of NOTCH1 in human HCC tissues as compared to control tissues. RT-PCR and Western blot quantification data showed that NOTCH1 and its downstream target transcription factor Hes1 were significantly upregulated in HCC cells. Based on these findings, we separated a population of CD44+ tumor-initiating cells (HepG2: >7%; SNU449: >6%) from HCC cell lines to ascertain the role of NOTCH1 in tumorigenesis. After NOTCH1-specific small interfering RNA (siRNA) transfection of tumor-initiating cells (TICs), NOTCH1 was significantly downregulated, and efficient uptake of DNA-targeting chemotherapeutic drugs was observed. Meanwhile, by flow cytometry analysis we found that the rate of apoptosis induction was significantly higher (P<0.01) and that cell viability was reduced (HepG2<23%; SNU449<28%) in siRNA transfected cells. In addition, the release of cytochrome C and activation of caspase 9 in CD44+ TICs was observed after siRNA transfection, confirming the induction of the mitochondrial-dependent intrinsic apoptotic pathway. Western blot analysis revealed inhibition of the PI3-Akt signaling pathway in siRNA-transfected TICs. These data suggest that activated NOTCH1 plays a significant role in liver cancer progression through apoptosis inhibition via regulation of PI3- Akt signaling. Therefore, pharmacological inactivation of NOTCH1 represents a clinically relevant therapeutic target for treating HCC.

scholarly journals Gambogic acid protects LPS-induced apoptosis and inflammation in a cell model of neonatal pneumonia through the regulation of TrkA/Akt signaling pathway

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xu Gao ◽  
Jingya Dai ◽  
Guifang Li ◽  
Xinya Dai
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Cell Model ◽  
Akt Signaling ◽  
Gambogic Acid ◽  
Akt Signaling Pathway ◽  
Western Blot Assay ◽  
A Cell ◽  
Induced Apoptosis ◽  
Apoptosis And Inflammation

Abstract Objective In this work, we investigated the effects of gambogic acid (GA) on lipopolysaccharide (LPS)-induced apoptosis and inflammation in a cell model of neonatal pneumonia. Method Human WI-38 cells were maintained in vitro and incubated with various concentrations of GA to examine WI-38 survival. GA-preincubated WI-38 cells were then treated with LPS to investigate the protective effects of GA on LPS-induced death, apoptosis and inflammation. Western blot assay was utilized to analyze the effect of GA on tropomyosin receptor kinase A (TrkA) signaling pathway in LPS-treated WI-38 cells. In addition, human AKT serine/threonine kinase 1 (Akt) gene was knocked down in WI-38 cells to further investigate the associated genetic mechanisms of GA in protecting LPS-induced inflammation and apoptosis. Results Pre-incubating WI-38 cells with low and medium concentrations GA protected LPS-induced cell death, apoptosis and inflammatory protein productions of IL-6 and MCP-1. Using western blot assay, it was demonstrated that GA promoted TrkA phosphorylation and Akt activation in LPS-treated WI-38 cells. Knocking down Akt gene in WI-38 cells showed that GA-associated protections against LPS-induced apoptosis and inflammation were significantly reduced. Conclusions GA protected LPS-induced apoptosis and inflammation, possibly through the activations of TrkA and Akt signaling pathway. This work may broaden our understanding on the molecular mechanisms of human neonatal pneumonia.

scholarly journals SU6668 modulates prostate cancer progression by downregulating MTDH/AKT signaling pathway

2017 ◽  
Vol 50 (5) ◽  
pp. 1601-1611 ◽  
Author(s):  
Benjiang Qian ◽  
Yi Yao ◽  
Changming Liu ◽  
Jiabing Zhang ◽  
Huihong Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Akt Signaling ◽  
Prostate Cancer Progression ◽  
Akt Signaling Pathway

scholarly journals Astragaloside positively regulated osteogenic differentiation of pre-osteoblast MC3T3-E1 through PI3K/Akt signaling pathway

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Wei Bing Jing ◽  
Hongjuan Ji ◽  
Rui Jiang ◽  
Jinlong Wang
Keyword(s):  
Western Blot ◽  
Osteogenic Differentiation ◽  
Real Time ◽  
Signaling Pathway ◽  
Real Time Pcr ◽  
Akt Signaling ◽  
Calcium Deposition ◽  
Control Group ◽  
Akt Signaling Pathway ◽  
Western Blot Assay

Abstract Background Osteoporosis is a widespread chronic disease characterized by low bone density. There is currently no gold standard treatment for osteoporosis. The aim of this study was to explore the role and mechanism of Astragaloside on osteogenic differentiation of MC3T3-E1 cells. Methods MC3T3-E1 cells were divided into control and different dose of Astragaloside (10, 20, 40, 50, and 60 μg/ml). Then, ALP and ARS staining were performed to identify the effects of Astragaloside for early and late osteogenic capacity of MC3T3-E1 cells, respectively. Real-time PCR and western blot were performed to assess the ALP, OCN, and OSX expression. PI3K/Akt signaling pathway molecules were then assessed by Western blot. Finally, PI3K inhibitor, LY294002, was implemented to assess the mechanism of Astragaloside in promoting osteogenic differentiation of MC3T3-E1 cells. Results Astragaloside significantly increased the cell viability than the control group. Moreover, Astragaloside enhanced the ALP activity and calcium deposition than the control groups. Compared with the control group, Astragaloside increased the ALP, OCN, and OSX expression in a dose-response manner. Western blot assay further confirmed the real-time PCR results. Astragaloside could significantly increase the p-PI3K and p-Akt expression than the control group. LY294002 partially reversed the promotion effects of Astragaloside on osteogenic differentiation of MC3T3-E1 cells. LY294002 partially reversed the promotion effects of Astragaloside on ALP, OCN, and OSX of MC3T3-E1 cells. Conclusion The present study suggested that Astragaloside promoted osteogenic differentiation of MC3T3-E1 cells through regulating PI3K/Akt signaling pathway.

scholarly journals Clinical significance of activated Wnt/β-catenin signaling in apoptosis inhibition of oral cancer

2021 ◽  
Vol 16 (1) ◽  
pp. 1045-1052
Author(s):  
Yufeng Wang ◽  
Zheng Cao ◽  
Fengjia Liu ◽  
Yuejian Ou
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Apoptotic Cell ◽  
Cancer Cell Proliferation ◽  
Rt Pcr ◽  
Sirna Transfection ◽  
Apoptosis Resistance ◽  
Apoptosis Inhibition ◽  
Anti Cancer ◽  
Evolutionarily Conserved

Abstract Wnt/β‐catenin signaling is an evolutionarily conserved pathway and plays a crucial role in regulating cancer cell proliferation and tumorigenesis. However, the molecular mechanism behind the Wnt/β‐catenin signaling-mediated carcinogenesis and apoptosis resistance in oral squamous cell carcinoma is not well characterized so far. In the present study, we have investigated the effect of β‐catenin depletion of the perversely activated Wnt/β-catenin signaling pathway on apoptosis resistance and tumorigenesis of the human OSCC cell line SCC-55. RT-PCR and western blot analysis demonstrated that the Wnt/β-catenin signaling pathway and its downstream targets such as DKK1 and AXIN2 are aberrantly activated in SCC-55 cells. Furthermore, upon silencing (RNA interference) of β‐catenin in SCC-55, cells became more sensitive toward the chemotherapeutic drugs and thus resulted in apoptotic cell death. Meanwhile, flow cytometry analysis confirmed the enhanced apoptosis and activation of caspases in β‐catenin RNAi cells. Besides ensuing β-catenin–siRNA transfection, the cell proliferation and cancer colony generating efficiencies are significantly impeded compared to the non-transfected cells. Furthermore, the tumorigenicity was inhibited by the downregulation of OCT-4 in β‐catenin-silenced SCC-55 cells. Altogether, Wnt/β‐catenin signaling could potentially target anti-cancer drugs to induce apoptosis and achieve a better clinical outcome.

Thidiazuron suppresses breast cancer progression via targeting miR-132 and miR-202-5p/PTEN axis mediated dysregulation of PI3K/AKT signaling pathway

2020 ◽  
Author(s):  
Hairul-Islam Ibrahim ◽  
Mohammad Bani Ismail ◽  
Rebai Ben Ammar ◽  
Emad Ahmed
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Metastatic Cancer ◽  
Akt Signaling ◽  
Breast Cancer Metastasis ◽  
Akt Signaling Pathway ◽  
Stressful Environment

Chemo-resistance and metastatic disease development are the most common causes of breast cancer recurrence and death. Thidiazuron (TDZ) is a plant growth regulator, its biological role on human and animals has not been yet clarified. In the present study, we investigated the anticancer activity of this plant phytohormone on the drug resistant-triple negative breast cancer MDA-MB-231 cell line. Treatment of the breast cancer cells with TDZ (1-50 μM) caused more stressful environment and induced a significant increase in percentages of active caspases positive cells. In addition, TDZ treatment (5 and 10 μM) significantly attenuated the migration and the invasion activities of these highly metastatic cancer cells. Mechanistically, TDZ reducesd cancer progression and invasive activity through targeting miR-202-5p, which stimulatesd the expression of the phosphatase and tensin homolog (PTEN), the tumor suppressor that downregulates PI3K/AKT signaling pathway. In the meantime, TDZ treatment statistically upregulatesd the suppressor of breast cancer proliferation, miRNA-132 that is also implicated in dysregulating the TEN-AKT/the nuclear factor NFκB signaling pathway. Interestingly, our molecular docking analysis revealed potential non-covalent interaction between TDZ with AKT, PTEN and PI3K. These findings suggest that TDZ may suppresses breast cancer metastasis through targeting miRNA-132, miR-202-5p/PTEN and PI3K/AKT downstream molecules.

scholarly journals SPON2 Is Upregulated through Notch Signaling Pathway and Promotes Tumor Progression in Gastric Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1439
Author(s):  
Hyeon-Gu Kang ◽  
Won-Jin Kim ◽  
Myung-Giun Noh ◽  
Kyung-Hee Chun ◽  
Seok-Jun Kim
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Notch Signaling Pathway ◽  
Migration And Invasion ◽  
Gene Assay ◽  
Gastric Cancer Progression

Spondin-2 (SPON2) is involved in cancer progression and metastasis of many tumors; however, its role and underlying mechanism in gastric cancer are still obscure. In this study, we investigated the role of SPON2 and related signaling pathway in gastric cancer progression and metastasis. SPON2 expression levels were found to be upregulated in gastric cancer cell lines and patient tissues compared to normal gastric epithelial cells and normal controls. Furthermore, SPON2 silencing was observed to decrease cell proliferation and motility and reduce tumor growth in xenograft mice. Conversely, SPON2 overexpression was found to increase cell proliferation and motility. Subsequently, we focused on regulatory mechanism of SPON2 in gastric cancer. cDNA microarray and in vitro study showed that Notch signaling is significantly correlated to SPON2 expression. Therefore, we confirmed how Notch signaling pathway regulate SPON2 expression using Notch signaling-related transcription factor interaction and reporter gene assay. Additionally, activation of Notch signaling was observed to increase cell proliferation, migration, and invasion through SPON2 expression. Our study demonstrated that Notch signaling-mediated SPON2 upregulation is associated with aggressive progression of gastric cancer. In conclusion, we suggest upregulated SPON2 via Notch signaling as a potential target gene to inhibit gastric cancer progression.

miR-184 Inhibits Hypertrophic Scar Through Regulating Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (AKT) Signaling Pathway

2020 ◽  
Vol 10 (1) ◽  
pp. 133-138
Author(s):  
Peng Zhao ◽  
Junxia Qin ◽  
Lili Liang ◽  
Xinzhong Zhang
Keyword(s):  
Cell Proliferation ◽  
Western Blot ◽  
Real Time ◽  
Signaling Pathway ◽  
Real Time Pcr ◽  
Hypertrophic Scar ◽  
Scar Tissue ◽  
Akt Signaling ◽  
Scar Formation ◽  
Akt Signaling Pathway

Hypertrophic scar (HS) is a process of tissue repair and healing, and excessive fibrosis of local tissue leads to scar formation. During HS formation, fibroblasts (Fb) proliferate, synthesize and secrete and promote HS development. miR-184 regulates skin formation and tissue development. However, miR-184’s role in HS remains unclear. miR-184 expression in HS patients and normal healthy (Control) tissues was measured by real-time PCR. pAKT expression was analyzed by Western blot. Fb cells from human HS were cultured and divided into 2 groups, siRNA NC group and miR-184 siRNA group followed by analysis of miR-184 expression by real time PCR, cell proliferation by MTT assay, secretion of inflammatory factors IL-1β and IL-6 by ELISA, as well as expression of pAKT and AKT by western blot. Compared with control group, miR-184 and pAKT expression was significantly increased in the HS group. Transfection of miR-184 siRNA into Fb significantly downregulated miR-184 expression, inhibited cell proliferation, promoted Caspase 3 activity, decreased IL-1β and IL-6 secretion, and reduced pAKT level (P < 0.05). miR-184 expression is increased in hypertrophic scar tissue. Down-regulation of miR-184 expression in proliferative scar tissue fibroblasts can down-regulate PI3K/AKT signaling pathway, inhibit inflammation, promote apoptosis, inhibit fibroblast proliferation, and regulate hypertrophic scar formation.

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