scholarly journals SERMs (selective estrogen receptor modulator), acting as estrogen receptor β agonists in hepatocellular carcinoma cells, inhibit the transforming growth factor-α-induced migration via specific inhibition of AKT signaling pathway

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262485
Author(s):  
Rie Matsushima-Nishiwaki ◽  
Noriko Yamada ◽  
Yuria Hattori ◽  
Yui Hosokawa ◽  
Junko Tachi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Estrogen Receptor ◽  
Cell Migration ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Receptor Modulator ◽  
Hcc Cells

Selective estrogen receptor modulator (SERM) interacts with estrogen receptors and acts as both an agonist or an antagonist, depending on the target tissue. SERM is widely used as a safer hormone replacement therapeutic medicine for postmenopausal osteoporosis. Regarding hepatocellular carcinoma (HCC), accumulating evidence indicates gender differences in the development, and that men are at higher morbidity risk than premenopausal women, suggesting that estrogen protects against HCC. However, it remains unclear whether SERM affects the HCC progression. Previously, we have shown that transforming growth factor (TGF)-α promotes the migration of HCC cells via p38 mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase and AKT. In the present study, we investigated whether SERM such as tamoxifen, raloxifene and bazedoxifene, affects the HCC cell migration using human HCC-derived HuH7 cells. Raloxifene and bazedoxifene but not tamoxifen, significantly suppressed the TGF-α-induced HuH7 cell migration. ERB041 and DPN, estrogen receptor (ER) β agonists, inhibited the TGF-α-induced cell migration whereas PPT, an ERα agonist, did not show the suppressive effect on the cell migration. ERB041 attenuated the TGF-α-induced phosphorylation of AKT without affecting the phosphorylation of p38 MAPK and c-Jun N-terminal kinase. Raloxifene and bazedoxifene also inhibited the phosphorylation of AKT by TGF-α. Furthermore, PHTPP, an ERβ antagonist, significantly reversed the suppression by both raloxifene and bazedoxifene of the TGF-α-induced cell migration. Taken together, our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-α-induced migration of HCC cells through ERβ-mediated inhibition of the AKT signaling pathway.

scholarly journals Vincosamide inhibits malignant behaviors of hepatocellular carcinoma cells by activating caspase-3 activity and blocking the PI3K/AKT signaling pathway

2020 ◽  
Author(s):  
Mingyue Zhu ◽  
Haipeng Feng ◽  
Bo Lin ◽  
Ying Zhou ◽  
Yifeng Zheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Tumor Model ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Mitochondrial Morphology ◽  
Mouse Tumor ◽  
Akt Signaling Pathway ◽  
Hcc Cells

Abstract Background Vincosamide(Vinco) was first identified in the methanolic extract of the leaves of Psychotria leiocarpa, and Vinco has important anti-inflammatory effects and activity against cholinesterase. However, whether Vinco inhibits the malignant behaviors of hepatocellular carcinoma(HCC) cells is still unclear. In the present study, we explored the role of Vinco in suppressing the malignant behaviors of HCC cells. Methods MTT and trypan blue exclusion assays were applied to detect the proliferation and death of HCC cells; electron microscopy was performed to observe change in cellular mitochondrial morphology; scratch repair and Transwell assays were used to analyze the migration and invasion of HCC cells; the expression and localization of proteins were detected by laser confocal microscopy and Western blotting; and the growth of the cancer cells in vivo was assessed in a mouse tumor model. Results At a dose of 10–80 µg/ml, Vinco inhibited the proliferation of HCC cells and promoted their apoptosis in a time- and dose-independent manner but had little effect on normal liver cells. Additionally, 80 µg/ml Vinco significantly disrupted the morphology of mitochondria and suppressed the migration and invasion of HCC cells. The growth of HCC cells in the animal tumor model was significantly inhibited after treatment with Vinco (10 mg/kg/day) for 3 days. The results of the present study indicate that Vinco (10–80 µg/ml) plays novel roles in activating caspase-3, promoting the expression of PTEN, and inhibiting the phosphorylation of AKT(Ser 473) and mTOR (Thr2448) and that Vinco was able to also suppress the expression of CXCR4, Src, MMP9, EpCAM, Ras and Oct4 in HCC cells. Conclusions Vinco plays a role in inhibiting the malignant behaviors of HCC cells, and the molecular mechanism may involve in suppressing the expression of the growth-, metastasis-related factors Src, Ras, MMP9, EpCAM and CXCR4 and activating the activity of caspase-3. Vinco also blocks the PI3K/AKT signaling pathway. Thus, Vinco is an available chemotherapy for HCC patients.

Vincosamide inhibits malignant behaviors of hepatocellular carcinoma cells by activating caspase-3 activity and blocking the PI3K/AKT signaling pathway

2020 ◽  
Author(s):  
Mingyue Zhu ◽  
Haipeng Feng ◽  
Bo Lin ◽  
Ying Zhou ◽  
Yifeng Zheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Akt Signaling ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Mitochondrial Morphology ◽  
Akt Signaling Pathway ◽  
Related Factors ◽  
Hcc Cells

Abstract Background: Vincosamide(Vinco) was first identified in the methanolic extract of the leaves of Psychotria leiocarpa, and Vinco has important anti-inflammatory effects and activity against cholinesterase, Vinco also has a trait to ant-tumor. However, whether Vinco is able to inhibit the malignant behaviors of hepatocellular carcinoma(HCC) cells is still unclear. In the present study, we explored the role of Vinco in suppressing the malignant behaviors of HCC cells.Methods: MTT, trypan blue exclusion assay and the Cell Counting Kit(CCK)-8 analysis were applied to detect the proliferation and death of HCC cells; electron microscopy was performed to observe the change of cellular mitochondrial morphology; scratch repair and Transwell assays were used to analyze the migration and invasion of HCC cells; the expression and localization of proteins were detected by laser confocal microscopy and Western blotting; and the growth of the cancer cells in in vivo was assessed in a mouse tumorous model.Results: At a dose of 10-80 mg/ml, Vinco inhibited the proliferation and promoted death of HCC cells in a dose-independent manner, but had low cytotoxcity effect on normal liver cells. Additionally, 80 mg/ml of Vinco could significantly disrupt the morphology of mitochondria, suppress the migration and invasion of HCC cells. The growth of HCC cells in the animal tumorous model was significantly inhibited after treatment with Vinco (10 mg/kg/day) for 3 days. The results of the present study indicated that Vinco (10-80 mg/ml) played a role in activating caspase-3, promoting the expression of PTEN, and inhibiting the phosphorylation of AKT(Ser473) and mTOR(Thr2448), Vinco also has a trait for suppressing the expression of CXCR4, Src, MMP9, EpCAM, Ras and Oct4 in HCC cells.Conclusions: Vinco has a role in inhibiting the malignant behaviors of HCC cells; the role molecular mechanism of Vinco maybe involve in restraining expression of the growth-, metastasis-related factors Src, Ras, MMP9, EpCAM and CXCR4, and activating the activity of caspase-3. Vinco also could block PI3K/AKT signaling pathway. Thus, Vinco is an available chemotherapy for HCC patients.

scholarly journals Astrocyte-Derived Transforming Growth Factor-β Mediates the Neuroprotective Effects of 17β-Estradiol: Involvement of Nonclassical Genomic Signaling Pathways

Endocrinology ◽  
2005 ◽  
Vol 146 (6) ◽  
pp. 2749-2759 ◽  
Author(s):  
Krishnan M. Dhandapani ◽  
F. Marlene Wade ◽  
Virendra B. Mahesh ◽  
Darrell W. Brann
Keyword(s):  
Estrogen Receptor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Neuronal Cell ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Cortical Astrocytes ◽  
Cortical Astrocyte ◽  
17Β Estradiol ◽  
The Brain

Abstract 17β-Estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen, mediate numerous effects in the brain, including neurosecretion, neuroprotection, and the induction of synaptic plasticity. Astrocytes, the most abundant cell type in the brain, influence many of these same functions and thus may represent a mediator of estrogen action. The present study examined the regulatory effect and underlying cell signaling mechanisms of E2-induced release of neurotropic growth factors from primary rat cortical astrocyte cultures. The results revealed that E2 (0.5, 1, and 10 nm) and tamoxifen (1 μm) increased both the expression and release of the neuroprotective cytokines, TGF-β1 and TGF-β2 (TGF-β), from cortical astrocytes. The stimulatory effect of E2 was attenuated by the estrogen receptor (ER) antagonist, ICI182,780, suggesting ER dependency. The effect of E2 also appeared to involve mediation by the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway, because E2 rapidly induced Akt phosphorylation, and pharmacological or molecular inhibition of the PI3K/Akt pathway prevented E2-induced release of TGF-β. Additionally, the membrane-impermeant conjugate, E2-BSA, stimulated the release of TGF-β, suggesting the potential involvement of a membrane-bound ER. Finally, E2, tamoxifen, and E2-BSA were shown to protect neuronal-astrocyte cocultures from camptothecin-induced neuronal cell death, effects that were attenuated by ICI182,780, Akt inhibition, or TGF-β immunoneutralization. As a whole, these studies suggest that E2 induction of TGF-β release from cortical astrocytes could provide a mechanism of neuroprotection, and that E2 stimulation of TGF-β expression and release from astrocytes occurs via an ER-dependent mechanism involving mediation by the PI3K/Akt signaling pathway.

scholarly journals Pharmacological Mechanisms Underlying the Hepatoprotective Effects of Ecliptae herba on Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Botao Pan ◽  
Wenxiu Pan ◽  
Zheng Lu ◽  
Chenglai Xia
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Network Pharmacology ◽  
Akt Signaling Pathway ◽  
Active Ingredients ◽  
Hepatoprotective Effects ◽  
Hcc Cells

Background. The number of hepatocellular carcinoma (HCC) cases worldwide has increased significantly. As a traditional Chinese medicine (TCM) with a long history, Ecliptae herba (EH) has been widely used in HCC patients in China, but its hepatoprotective mechanism is still unclear. Methods. In this study, we applied a network pharmacology-based strategy and experimental verification to systematically unravel the underlying mechanisms of EH against HCC. First, six active ingredients of EH were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) by the ADME method. Subsequently, 52 potential targets of 6 active ingredients acting on HCC were screened from various databases, including TCMSP, DGIdb, SwissTargetPrediction, CTD, and GeneCards. Then, by constructing protein-protein interaction (PPI) network from STRING, we displayed the intricate connections among these 52 targets through Cytoscape software. We also applied enrichment analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, to provide an outline and set of concepts for describing gene functions and the advanced functions of biological systems of these 52 targets from genomic and molecular level information. Finally, molecular docking and biological experiments were used to reconfirm these results. Results. We hypothesized that EH might exert anti-HCC activity by acting on hub genes, including RELA, MMP9, PTGS2, ESR1, EGFR, AR, AKT1, HIF1A, AHR, CYP3A4, ABCG2, and MMP2. Moreover, based on GO and KEGG analysis, we speculated that EH may exert hepatoprotective effects on HCC through the following mechanisms: regulation of the PI3K-AKT signaling pathway to promote apoptosis and inhibit the abnormal proliferation of HCC, downregulation of HIF-1A expression by activating the HIF-1 signaling pathway, prevention of HCC by regulating lipid metabolism, and inhibition of nonalcoholic fatty liver disease (NAFLD) by the cytochrome P450 subfamily. Subsequent biological experiments verified that EH inhibits the PI3K-AKT signaling pathway through its active ingredients, quercetin, and wedelolactone, thereby inhibiting the proliferation of HCC cells and promoting the apoptosis of HCC cells. Conclusions. The network pharmacological strategy provides an efficient method to systematically explore the pharmacological mechanism of EH in HCC. Our study demonstrated that the anti-HCC proliferation activity of EH is mainly exerted by two active ingredients (quercetin and wedelolactone), which inhibit the proliferation of HCC cells (HepG2 and Huh-7) by inhibiting PI3K-AKT signaling.

scholarly journals Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition

2021 ◽  
Vol 9 ◽  
Author(s):  
Cong Wang ◽  
Chuzhi Shang ◽  
Xiaohong Gai ◽  
Tao Song ◽  
Shaoshan Han ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Epithelial To Mesenchymal Transition ◽  
Akt Signaling ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter ◽  
Akt Signaling Pathway ◽  
Mesenchymal Transition ◽  
Hcc Cells

BackgroundSulfatase 2 (SULF2) removes the 6-O-sulfate groups from heparan sulfate proteoglycans (HSPG) and consequently alters the binding sites for various signaling molecules. Here, we elucidated the role of SULF2 in the differentiation of hepatic stellate cells (HSCs) into carcinoma-associated fibroblasts (CAFs) in the hepatocellular carcinoma (HCC) microenvironment and the mechanism underlying CAF-mediated HCC growth.MethodsThe clinical relevance of SULF2 and CAFs was examined using in silico and immunohistochemical (IHC) analyses. Functional studies were performed to evaluate the role of SULF2 in the differentiation of HSCs into CAFs and elucidate the mechanism underlying CAF-mediated HCC growth. Mechanistic studies were performed using the chromatin immunoprecipitation, luciferase reporter, and RNA immunoprecipitation assays. The in vitro findings were verified using the nude HCC xenograft mouse model.ResultsThe Cancer Genome Atlas (TCGA) database and IHC analyses revealed that the expression of CAF markers, which was positively correlated with that of SULF2 in the HCC tissues, predicted unfavorable postsurgical outcomes. Co-culturing HSCs with HCC cells expressing SULF2 promoted CAF differentiation. Additionally, CAFs repressed HCC cell apoptosis by activating the SDF-1/CXCR4/PI3K/AKT signaling pathway. Meanwhile, SULF2-induced CAFs promoted epithelial-to-mesenchymal transition (EMT) of HCC cells by modulating the SDF-1/CXCR4/OIP5-AS1/miR-153-3p/SNAI1 axis. Studies using HCC xenograft mouse models demonstrated that OIP5-AS1 induced EMT by upregulating SNAI1 and promoted HCC growth in vivo.ConclusionThese data indicated that SULF2 secreted by the HCC cells induced the differentiation of HSCs into CAFs through the TGFβ1/SMAD3 signaling pathway. SULF2-induced CAFs attenuated HCC apoptosis by activating the SDF-1/CXCR4/PI3K/AKT signaling pathway and induced EMT through the SDF-1/CXCR4/OIP5-AS1/miR-153-3p/SNAI1 axis. This study revealed a novel mechanism involved in the crosstalk between HCC cells and CAFs in the tumor microenvironment, which can aid in the development of novel and efficient therapeutic strategies for primary liver cancer.

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