scholarly journals Dihydroartemisinin Sensitizes Mutant p53 (R248Q)-Expressing Hepatocellular Carcinoma Cells to Doxorubicin by Inhibiting P-gp Expression

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Yue Yang ◽  
Jianxin He ◽  
Jing Chen ◽  
Li Lin ◽  
Yongqi Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Chemotherapeutic Agents ◽  
Carcinoma Cells ◽  
Mutant P53 ◽  
Hep3b Cells ◽  
Dynamics Simulations ◽  
Apoptosis Level ◽  
Hcc Cells

Mutant p53 (R248Q) induces doxorubicin (ADM) resistance in hepatocellular carcinoma (HCC). Dihydroartemisinin (DHA) can synergistically enhance anticancer effect of many chemotherapeutic agents. However, whether DHA could increase therapeutic efficacy of ADM in p53 (R248Q)-expressing HCC cells remains unknown. In the present study, we established mutant p53 (R248Q)-expressing Hep3B cells to study the effect and mechanism of DHA on ADM resistance and the synergistic effect of DHA with ADM. We found that P-gp was highly expressed in p53 (R248Q)-expressing Hep3B cells. As a result, cells expressing p53 (R248Q) displayed higher cell viability and lower cell apoptosis level upon ADM treatment. Meanwhile, phosphorylation levels of ERK1/2 and p65 were elevated in p53 (R248Q)-expressing Hep3B cells. However, combination of DHA and ADM treatment decreased cell viability and elevated cell apoptosis level in p53 (R248Q)-expressing Hep3B cells. Molecular dynamics simulations showed that DHA had the potential to bind with mutant p53 (R248Q) protein. Furthermore, DHA treatment decreased P-gp expression and inhibited phosphorylation levels of ERK1/2 and p65 in p53 (R248Q)-expressing Hep3B cells. Finally, DHA treatment could significantly reduce ADM efflux in p53 (R248Q)-expressing cells. Our results indicate that DHA could decrease P-gp expression via inhibiting the p53 (R248Q)-ERK1/2-NF-κB signaling pathway, which eventually confers sensitization of p53 (R248Q)-expressing HCC cells to ADM. Our study provides evidence for the potential application of DHA and ADM combination in treatment of mutant p53 (R248Q)-harbored HCC.

scholarly journals Inhibition of protein phosphatase 1 stimulates noncanonical ER stress eIF2α activation to enhance fisetin-induced chemosensitivity in HDAC inhibitor-resistant hepatocellular carcinoma cells

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 918 ◽  
Author(s):  
Liu ◽  
Yu-Chun ◽  
Chang ◽  
Kuo ◽  
Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Phosphatase ◽  
Cell Apoptosis ◽  
Histone Deacetylase Inhibitors ◽  
Molecular Mechanisms ◽  
Chemotherapeutic Agents ◽  
Protein Phosphatase 1 ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is a common fatal type of malignant tumor that has highly metastatic and recurrent properties. Fisetin is a natural flavonoid found in various vegetables and fruits which exhibits anti-cancer and anti-inflammatory properties, as well as other effects. Thus, we hypothesized that fisetin can act as an adjuvant therapy in cancer or drug-resistant cancer cells, and further investigated the molecular mechanisms underlying the development of drug-resistance in HCC cells. We found that fisetin effectively inhibited the cell viability of not only parental cells but also histone deacetylase inhibitors-resistant (HDACis-R) cells and enhanced the chemosensitivity of HCC cells. Interestingly, fisetin did not induce cell apoptosis through the activation of the endoplasmic reticulum (ER) stress sensor of protein kinase R (PKR)-like endoplasmic reticulum kinase, but rather through the non-canonical pathway of the protein phosphatase 1 (PP1)-mediated suppression of eIF2α phosphorylation. Moreover, fisetin-induced cell apoptosis was reversed by treatment with PP1 activator or eIF2α siRNA in HCC cells. Based on these observations, we suggest that PP1-eIF2α pathways are significantly involved in the effect of fisetin on HCC apoptosis. Thus, fisetin may act as a novel anticancer drug and new chemotherapy adjuvant which can improve the efficacy of chemotherapeutic agents and diminish their side-effects.

scholarly journals Fibrinogen-Like Protein 1 Modulates Sorafenib Resistance in Human Hepatocellular Carcinoma Cells

2021 ◽  
Vol 22 (10) ◽  
pp. 5330
Author(s):  
Yeonghoon Son ◽  
Na-Rae Shin ◽  
Sung-Ho Kim ◽  
Su-Cheol Park ◽  
Hae-June Lee
Keyword(s):  
Hepatocellular Carcinoma ◽  
Flow Cytometry ◽  
Colony Formation ◽  
Anticancer Therapy ◽  
Carcinoma Cells ◽  
Hep3b Cells ◽  
Human Hepatocellular Carcinoma Cells ◽  
Systemic Drug ◽  
Higher Sensitivity ◽  
Hcc Cells

Despite liver cancer being the second-leading cause of cancer-related death worldwide, few systemic drugs have been approved. Sorafenib, the first FDA-approved systemic drug for unresectable hepatocellular carcinoma (HCC), is limited by resistance. However, the precise mechanisms underlying this phenomenon are unknown. Since fibrinogen-like 1 (FGL1) is involved in HCC progression and upregulated after anticancer therapy, we investigated its role in regulating sorafenib resistance in HCC. FGL1 expression was assessed in six HCC cell lines (HepG2, Huh7, Hep3B, SNU387, SNU449, and SNU475) using western blotting. Correlations between FGL1 expression and sorafenib resistance were examined by cell viability, colony formation, and flow cytometry assays. FGL1 was knocked-down to confirm its effects on sorafenib resistance. FGL1 expression was higher in HepG2, Huh7, and Hep3B cells than in SNU387, SNU449, and SNU475 cells; high FGL1-expressing HCC cells showed a lower IC50 and higher sensitivity to sorafenib. In Huh7 and Hep3B cells, FGL1 knockdown significantly increased colony formation by 61% (p = 0.0013) and 99% (p = 0.0002), respectively, compared to that in controls and abolished sorafenib-induced suppression of colony formation, possibly by modulating ERK and autophagy signals. Our findings demonstrate that sorafenib resistance mediated by FGL1 in HCC cells, suggesting FGL1 as a potential sorafenib-resistance biomarker and target for HCC therapy.

scholarly journals Three New Iridoid Derivatives Have Been Isolated from the Stems of Neonauclea reticulata (Havil.) Merr. with Cytotoxic Activity on Hepatocellular Carcinoma Cells

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2297 ◽  
Author(s):  
Fang-Pin Chang ◽  
Wei Chao ◽  
Sheng-Yang Wang ◽  
Hui-Chi Huang ◽  
Ping-Jyun Sung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Abscisic Acid ◽  
Cytotoxic Activity ◽  
Spectroscopic Data ◽  
Carcinoma Cells ◽  
Coumaric Acid ◽  
Cytotoxic Assay ◽  
Hep3b Cells ◽  
Hcc Cells

Three new iridoids, namely neonanin A (1), neonanin B (2) and neoretinin A (3), as well as twelve known compounds, 6-hydroxy-7-methyl-1-oxo-4-carbomethoxyoctahydrocyclopenta[c]pyran (4), 4-epi-alyxialactone (5), loganetin (6), loganin (7), phenylcoumaran-α′-aldehyde (8), cleomiscosin A (9), ficusal (10), balanophonin (11), vanillic acid (12), p-coumaric acid (13), cis,trans-abscisic acid (14), and trans,trans-abscisic acid (15) were isolated from the stems of Neonauclea reticulata (Havil.) Merr. These new structures were determined by the detailed analysis of spectroscopic data and comparison with the data of known analogues. Compounds 1–13 were evaluated using an in-vitro MTT cytotoxic assay for hepatocellular carcinoma (HCC) cells, and the preliminary results showed that ficusal (10), balanophonin (11), and p-coumaric acid (13) exhibited moderate cytotoxic activity, with EC50 values of 85.36 ± 4.36, 92.63 ± 1.41, and 29.18 ± 3.48 µg/mL against Hep3B cells, respectively.

Sufentanil Inhibits Proliferation, Migration, and Invasion of Hepatocellular Carcinoma Cells by Upregulating miRNA-204

2021 ◽  
Vol 11 (4) ◽  
pp. 718-724
Author(s):  
Jiuwu Zhuo ◽  
Yishan Zheng ◽  
Wanying Hu ◽  
Guoping Yin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Biological Function ◽  
Transfection Efficiency ◽  
Carcinoma Cells ◽  
Migration And Invasion ◽  
Qrt Pcr ◽  
Pi3k Signaling Pathway ◽  
Hep3b Cells ◽  
Underlying Mechanisms ◽  
Hcc Cells

Sufentanil is a powerful analgesic that acts on μ-receptors, but there are few studies on sufentanil in cancer. The biological function and underlying mechanisms of sufentanil on the hepatocellular carcinoma (HCC) cells were explored in the present study. HCC cells were first treated with different concentrations of sufentanil and the most optimum concentration of sufentanil was determined. The expression of miR-204 in HCC cells was changed by transfected with miR-204 inhibitor and the transfection efficiency was assessed by qRT-PCR. CCK-8, wound-healing and Transwell assays were performed to evaluate the proliferation, migration and invasion of HCC cells, respectively. The level of AKT and PI3K phosphorylation (p-AKT and p-PI3K) were assessed by western blot analysis. Our results demonstrated that sufentanil effectively inhibited cell proliferation,migration and invasion in both Huh7 and Hep3B cells, and significantly decreased the expression of p-AKT and p-PI3K. In addition, miR-204 was upregulated in Huh7 and Hep3B cells treated with sufentanil, and low expression of miR-204 attenuated the damage of sufentanil on the viability of Huh7 and Hep3B cells. Taken together, sufentanil suppressed the proliferation, migration and invasion of HCC cells via inhibiting AKT/PI3K signaling pathway by targeting miR-204.

MiRNA-485-5p inhibited the proliferation and promoted the apoptosis of hepatocellular carcinoma cells by targeting MUC1

2020 ◽  
Author(s):  
Ming Li ◽  
Dong Zhu ◽  
Xiaozhen Peng ◽  
Pinyue Liu ◽  
Fen Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Western Blot ◽  
Binding Site ◽  
Cell Apoptosis ◽  
Carcinoma Cells ◽  
Luciferase Assay ◽  
Adjacent Tissue ◽  
Dual Luciferase Assay ◽  
Hcc Cells

Abstract Background The downregulation of miRNA-485-5-p was related to prognosis of various cancers, including hepatocellular carcinoma (HCC), while MUC1 was aberrantly expressed in many cancers and could be a biomarker for prognosis and diagnosis of cancers. The aim of the study was to investigate whether the miRNA-485-5p inhibited proliferation and promoted apoptosis by targeting MUC1 in HCC cells.Methods The expression of miRNA-485-5p in patients with HCC was measured by qPCR, and the epxression of MUC1 was detected by qPCR, western blot and immunohistochemistry. Bioinformatics and dual luciferase assay verified the targeting relationship between miRNA-485-5p and MUC1 in HCC cells. Cell proliferation was detected by CCK-8 assay. Cell apoptosis was detected by flow cytometry.Results The expression of miRNA-485-5p in HCC tissues is downregulated than that in adjacent tissue. However, the exprssion of MUC1 is opposite to the expression of miRNA-485-5p in the patients with HCC. Silencing MUC1 and overexpression miRNA-485-5p both inhibit proliferation and promote apoptosis in HCC cells. MiRNA-485-5p directly targete to the binding site of the MUC1 3’UTR and downregulated the expression of MUC1. Overexpression of MUC1 and miRNA-485-5p reverse the effect of miRNA-485-5p on the cell proliferation and apoptosis.Conclusion MiRNA-485-5p inhibits the proliferation and facilitates the apoptosis by negatively regulating the expression of MUC1 in HCC cells.

scholarly journals Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3

2021 ◽  
Vol 22 (9) ◽  
pp. 4743
Author(s):  
Il Je Cho ◽  
Jae Kwang Kim ◽  
Eun Ok Kim ◽  
Sang Mi Park ◽  
Sang Chan Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Annexin V ◽  
Chemotherapeutic Agents ◽  
Carcinoma Cells ◽  
Tunel Staining ◽  
Cytotoxic Effects ◽  
Beneficial Effects ◽  
Transcription 3 ◽  
Hcc Cells

Hemistepta lyrata (Bunge) Bunge is a biennial medicinal plant possessing beneficial effects including anti-inflammation, and hemistepsin A (HsA) isolated from H. lyrata has been known as a hepatoprotective sesquiterpene lactone. In this report, we explored the cytotoxic effects of H. lyrata on hepatocellular carcinoma (HCC) cells and investigated the associated bioactive compounds and their relevant mechanisms. From the viability results of HCC cells treated with various H. lyrata extracts, HsA was identified as the major compound contributing to the H. lyrata-mediated cytotoxicity. HsA increased expression of cleaved PARP and cells with Sub-G1 phase, Annexin V binding, and TUNEL staining, which imply HsA induces apoptosis. In addition, HsA provoked oxidative stress by decreasing the reduced glutathione/oxidized glutathione ratio and accumulating reactive oxygen species and glutathione-protein adducts. Moreover, HsA inhibited the transactivation of signal transducer and activator of transcription 3 (STAT3) by its dephosphorylation at Y705 and glutathione conjugation. Stable expression of a constitutive active mutant of STAT3 prevented the reduction of cell viability by HsA. Finally, HsA enhanced the sensitivity of sorafenib-mediated cytotoxicity by exaggerating oxidative stress and Y705 dephosphorylation of STAT3. Therefore, HsA will be a promising candidate to induce apoptosis of HCC cells via downregulating STAT3 and sensitizing conventional chemotherapeutic agents.

scholarly journals Intracellular alpha-fetoprotein interferes with all-trans retinoic acid induced ATG7 expression and autophagy in hepatocellular carcinoma cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shanshan Wang ◽  
Rilu Feng ◽  
Ying Shi ◽  
Dexi Chen ◽  
Honglei Weng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Retinoic Acid ◽  
Carcinoma Cells ◽  
Alpha Fetoprotein ◽  
Cell Counting ◽  
All Trans Retinoic Acid ◽  
Induced Apoptosis ◽  
Anti Tumor Activity ◽  
Retinoid Acid ◽  
Hcc Cells

AbstractRetinoic acid and retinoid acid receptor (RA-RAR) signaling exhibits suppressive functions in the progression of hepatocellular carcinoma (HCC) through multiple mechanisms. However, whether RA-RAR signaling induces autophagy that contributes its anti-tumor activity in HCC remains elusive. In the current study, the effects of RA-RAR pathway on autophagy were investigated in two HCC cell lines: alpha-fetoprotein (AFP) positive PLC/PRF/5 and AFP negative HLE cells. Cell autophagy was analyzed with western blot for detection of LC3 conversion and p62/SQSTM1 degradation while autophagy flux was assayed using the mRFP-GFP-LC3 reporter. Cell apoptosis and viability were analyzed by caspase-3 activity, TdT-mediated dUTP nick end labeling (TUNEL) assay, and Cell Counting Kit (CCK)-8, respectively. Chromatin immunoprecipitation (ChIP) was employed to detect the binding of RAR onto the promoter of autophagy-relevant 7 (ATG7), and co-immunoprecipitation (CoIP) was used to analyze the interaction of AFP and RAR. The results showed that ATRA dosage and time-dependently induced high levels of cell autophagy in both the PLC/PRF/5 and HLE cells, which was accompanied with up-regulation of ATG7. ChIP assay showed that RAR was able to bind to its responsive elements on ATG7 promoter. Impairment of ATG7 induction or blockade of autophagy with chloroquine aggravated ATRA induced apoptosis of HCC cells. Furthermore, intracellular AFP was able to complex with RAR in PLC/PRF/5 cells. Knockdown of AFP in PLC/PRF/5 cells augmented the up-regulation of ATG7 by ATRA while overexpression of AFP in HLE cells attenuated ATRA induced ATG7 expression and autophagy. Thus, ATRA induced ATG7 and autophagy participated in its cytotoxicity on HCC cells and AFP interfere with the induction of ATG7 and autophagy through forming complex with RAR.

Sign in / Sign up

Export Citation Format

Share Document