scholarly journals Anticancer and Antiangiogenic Activities of Novel α-Mangostin Glycosides in Human Hepatocellular Carcinoma Cells via Downregulation of c-Met and HIF-1α

2020 ◽  
Vol 21 (11) ◽  
pp. 4043
Author(s):  
Sung Min Kim ◽  
Jang Mi Han ◽  
Tuoi Thi Le ◽  
Jae Kyung Sohng ◽  
Hye Jin Jung
Keyword(s):  
Hepatocellular Carcinoma ◽  
Anticancer Agents ◽  
Apoptotic Cell ◽  
Primary Liver Cancer ◽  
Critical Role ◽  
Single Agent ◽  
Hep3b Cell ◽  
Parent Molecule ◽  
Hep3b Cells ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Therefore, exploring effective anticancer agents and their modes of action is essential for the prevention and treatment of HCC. Glycosylation can significantly improve the physicochemical and biological properties of small molecules, such as high solubility, stability increase, and lower toxicity. In the present study, for the first time, we evaluated the anticancer and antiangiogenic activities of α-mangostin-3-O-β-D-2-deoxyglucopyranoside (Man-3DG) and α-mangostin 6-O-β-D-2-deoxyglucopyranoside (Man-6DG), glycosides of α-mangostin, against human HCC cells. Our results demonstrated that Man-3DG and Man-6DG significantly suppressed the growth of three different HCC cells (Hep3B, Huh7, and HepG2) as well as the migration of Hep3B cells. Furthermore, they induced cell cycle arrest in the G0/G1 phases and apoptotic cell death by regulating apoptosis-related proteins of mitochondria in Hep3B cells. Noticeably, Man-3DG and Man-6DG also caused autophagy, while co-treatment of the α-mangostin glycosides with an autophagy inhibitor 3-MA enhanced the inhibitory effect on Hep3B cell growth in comparison to single agent treatment. Moreover, Man-3DG and Man-6DG inhibited the c-Met signaling pathway that plays a critical role in the pathogenesis of HCC. Furthermore, the α-mangostin glycosides decreased Hep3B cell-induced angiogenesis in vitro through the downregulation of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Notably, Man-6DG more effectively inhibited the growth, tumorsphere formation, and expression of cancer stemness regulators compared to α-mangostin and Man-3DG in 3D spheroid-cultured Hep3B cells. These findings suggest that the α-mangostin glycosides might be promising anticancer agents for HCC treatment with superior pharmacological properties than the parent molecule α-mangostin.

scholarly journals Anticancer Activities and Underlying Molecular Mechanisms of Novel Mangostin Glycosides in Human Hepatocellular Carcinoma Hep3B Cells

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 5
Author(s):  
Kim ◽  
Han ◽  
Jung
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Anticancer Agents ◽  
Molecular Mechanisms ◽  
Primary Liver Cancer ◽  
Critical Role ◽  
Single Agent ◽  
Anticancer Activities ◽  
Parent Molecule ◽  
Hep3b Cells

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Therefore, exploring effective anticancer agents and their modes of action is essential for the prevention and treatment of HCC. Glycosylation can significantly improve the physicochemical and biological properties of small molecules, such as high solubility, stability increase, and lower toxicity. In this study, for the first time, we evaluated the anticancer activities of mangostin-3-O-β-d-2-deoxyglucopyranoside (Man-3DG) and mangostin 6-O-β-d-2-deoxyglucopyranoside (Man-6DG), glycosides of mangostin, against human hepatoma Hep3B cells. Our results demonstrated that Man-3DG and Man-6DG significantly suppressed growth and migration of Hep3B cells. In addition, they induced apoptosis of Hep3B cells by regulating apoptosis-related proteins of mitochondria. Noticeably, Man-3DG and Man-6DG also caused autophage, while cotreatment of the mangostin glycosides with an autophage inhibitor 3MA enhanced the inhibitory effect on Hep3B cell growth, compared to single agent treatment. Moreover, Man-3DG and Man-6DG inhibited the c-Met signaling pathway, which plays a critical role in the pathogenesis of liver cancer. Furthermore, the mangostin glycosides decreased tumor cell-induced angiogenesis in vitro through downregulation of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). These findings suggest that Man-3DG and Man-6DG might be promising anticancer agents for HCC treatment with superior pharmacological properties than parent molecule mangostin.

scholarly journals Bromodomain-containing protein 9 promotes the growth and metastasis of human hepatocellular carcinoma by activating the TUFT1/AKT pathway

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Changwei Dou ◽  
Liankang Sun ◽  
Liang Wang ◽  
Jian Cheng ◽  
Weiding Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Disease Free Survival ◽  
Akt Pathway ◽  
Akt Inhibitor ◽  
Mesenchymal Transition ◽  
Hep3b Cells ◽  
Hcc Cells

Abstract Bromodomain-containing protein 9 (BRD9) has a critical role in human squamous cell lung cancer, acute myeloid leukemia, and malignant rhabdoid tumors. However, the expression and biological role of BRD9 in hepatocellular carcinoma (HCC) is poorly understood. In this study, BRD9 expression was found to be elevated in HCC through data mining of public databases. Next, we confirmed that the expression of BRD9 was increased in HCC tissues compared with that in adjacent non-tumor tissues. The upregulated level of BRD9 was also observed in HCC cells in comparison to LO2 cells. The increased BRD9 expression was correlated with unfavorable clinicopathological features. A high level of BRD9 predicted a poorer overall survival and disease-free survival of HCC patients. Functionally, BRD9 overexpression facilitated the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of Hep3B cells. Conversely, either BRD9 depletion or pharmacological inhibition of BRD9 resulted in the reduced proliferation and invasiveness of HCCLM3 cells. In addition, the BRD9 knockdown restrained the growth and metastasis of HCCLM3 cells in vivo. Mechanistically, BRD9 positively regulated TUFT1 expression and AKT activation in HCC cells. ChIP-qPCR analysis indicated that BRD9 promoted the binding of P300 acetyltransferase to the TUFT1 promoter and epigenetically regulated TUFT1 expression by increasing H3K27Ac in the promoter. Notably, either TUFT1 knockdown or AKT inhibitor (MK2206) abrogated the promoting effects of BRD9 on the proliferation, migration, invasion, and EMT of Hep3B cells. The forced expression of TUFT1 abolished the effects of BRD9 knockdown on the growth and metastasis of HCCLM3 cells. Altogether, these data indicate that BRD9 promotes the growth and metastasis of HCC cells by activating the TUFT1/AKT pathway and may serve as a promising biomarker and therapeutic target for HCC.

scholarly journals The Natural Pigment Violacein Potentially Suppresses the Proliferation and Stemness of Hepatocellular Carcinoma Cells In Vitro

2021 ◽  
Vol 22 (19) ◽  
pp. 10731
Author(s):  
Yu Jin Kim ◽  
Nayeong Yuk ◽  
Hee Jeong Shin ◽  
Hye Jin Jung
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Potential ◽  
Apoptotic Cell ◽  
Primary Liver Cancer ◽  
Therapeutic Effects ◽  
Bacterial Strains ◽  
Nuclear Condensation ◽  
Incidence And Mortality ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is a malignant type of primary liver cancer with high incidence and mortality, worldwide. A major challenge in the treatment of HCC is chemotherapeutic resistance. It is therefore necessary to develop novel anticancer drugs for suppressing the growth of HCC cells and overcoming drug resistance for improving the treatment of HCC. Violacein is a deep violet-colored indole derivative that is produced by several bacterial strains, including Chromobacterium violaceum, and it possesses numerous pharmacological properties, including antitumor activity. However, the therapeutic effects of violacein and the mechanism underlying its antitumor effect against HCC remain to be elucidated. This study is the first to demonstrate that violacein inhibits the proliferation and stemness of Huh7 and Hep3B HCC cells. The antiproliferative effect of violacein was attributed to cell cycle arrest at the sub-G1 phase and the induction of apoptotic cell death. Violacein induced nuclear condensation, dissipated mitochondrial membrane potential (MMP), increased generation of reactive oxygen species (ROS), activated the caspase cascade, and upregulated p53 and p21. The anticancer effect of violacein on HCC cells was also associated with the downregulation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2 signaling. Violacein not only suppressed the proliferation and formation of tumorspheres of Huh7 and Hep3B cancer stem-like cells but also reduced the expression of key markers of cancer stemness, including CD133, Sox2, Oct4, and Nanog, by inhibiting the signal transducer and activator of transcription 3 (STAT3)/AKT/ERK pathways. These results suggest the therapeutic potential of violacein in effectively suppressing HCC by targeting the proliferation and stemness of HCC cells.

scholarly journals Regulation of TREM1-Mediated Inflammation in Hepatocellular Carcinoma Cells

Reports ◽  
2021 ◽  
Vol 4 (2) ◽  
pp. 17
Author(s):  
Vikrant Rai ◽  
Devendra K. Agrawal
Keyword(s):  
Hepatocellular Carcinoma ◽  
Vitamin D ◽  
Chronic Inflammation ◽  
Therapeutic Target ◽  
Primary Liver Cancer ◽  
Migration And Invasion ◽  
Potential Therapeutic Target ◽  
Mediators Of Inflammation ◽  
Tnf Α ◽  
Hcc Cells

Hepatocellular carcinoma (HCC), accounting for more than 90% of cases of primary liver cancer, is the third most common cause of cancer-related death worldwide. Chronic inflammation precedes the development of cirrhosis and HCC. TREM (triggering receptor expressed on myeloid cell)-1 is an inflammatory marker and amplifier of inflammation that signals through PI3K and ERK1/2 to activate transcription factors, resulting in increased secretion of pro-inflammatory cytokines, causing chronic inflammation and predisposing the liver to carcinogenesis. Thus, targeting TREM-1 in HCC might be a potential therapeutic target. A low level of vitamin D has been associated with chronic inflammation and poor prognosis in HCC. Thus, we evaluated the effect of vitamin D on TREM-1 expression in the HCC cell line. Additionally, the effects of high mobility group box-1, lipopolysaccharide, and transcription factor PU.1 on the expression of TREM-1 in normal liver cells and HCC cells have been investigated in the presence and absence of vitamin D. The results showed increased expression of TREM-1 in HCC cells and with IL-6, TNF-α, LPS, and rHMGB-1 and decreased expression with calcitriol. Calcitriol also attenuated the effect of IL-6, TNF-α, LPS, and rHMGB-1 on TREM-1. Calcitriol treatment attenuated the proliferation, migration, and invasion of HCC cells. These results (in vitro) provide molecular and biochemical evidence that calcitriol significantly attenuates the expression of mediators of inflammation, and thus might be used therapeutically together with conventional treatment to delay the progression of HCC. Additionally, the negative regulation of TREM-1 by PU.1 suggests PU.1 as a potential therapeutic target.

scholarly journals Long non-coding RNA TUG1 promotes cell progression in hepatocellular carcinoma via regulating miR-216b-5p/DLX2 axis

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Qun Dai ◽  
Jingyi Deng ◽  
Jinrong Zhou ◽  
Zhuhong Wang ◽  
Xiao-feng Yuan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Marked Rise ◽  
Hcc Cells

Abstract Background Accumulating evidence indicates that the long noncoding RNA taurine upregulated gene 1(TUG1) plays a critical role in cancer progression and metastasis. However, the overall biological role and clinical significance of TUG1 in hepatocellular carcinoma (HCC) remain largely unknown. Methods The expressions of TUG1, microRNA-216b-5p and distal-less homeobox 2 (DLX2) were detected by Quantitative real-time polymerase chain reaction (qRT-PCR). The target relationships were predicted by StarBase v.2.0 or TargetScan and confirmed by dual-luciferase reporter assay. The cell growth, apoptosis, migration and invasion were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Flow cytometry and Transwell assays, respectively. All protein expression levels were detected by western blot. Tumor xenografts were implemented to explore the role of TUG1 in vivo. Results We found that there was a marked rise in TUG1 expression in HCC tissues and cells, and knockdown of TUG1 repressed the growth and metastasis and promoted apoptosis of HCC cells. In particular, TUG1 could act as a ceRNA, effectively becoming a sink for miR-216b-5p to fortify the expression of DLX2. Additionally, repression of TUG1 impared the progression of HCC cells by inhibiting DLX2 expression via sponging miR-216b-5p in vitro. More importantly, TUG1 knockdown inhibited HCC tumor growth in vivo through upregulating miR-216b-5p via inactivation of the DLX2. Conclusion TUG1 interacting with miR-216b-5p contributed to proliferation, metastasis, tumorigenesis and retarded apoptosis by activation of DLX2 in HCC.

scholarly journals PITPNA-AS1 abrogates the inhibition of miR-876-5p on WNT5A to facilitate hepatocellular carcinoma progression

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Jianmin Sun ◽  
Yubao Zhang ◽  
Bing Li ◽  
Yuandi Dong ◽  
Chengming Sun ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Treatment Strategies ◽  
Diagnostic Biomarkers ◽  
Cellular Processes ◽  
Candidate Mirnas ◽  
In Vivo Experiments ◽  
Wnt5a Expression ◽  
Hep3b Cells ◽  
Hcc Cells

Abstract LncRNA PITPNA-AS1 was a newly identified lncRNA which has never been studied in cancers. Whether PITPNA-AS1 participated in the development of hepatocellular carcinoma (HCC) is obscure. Given the coaction of lncRNAs and miRNAs to carcinogenesis, the purpose of the present research is to inquire how PITPNA-AS1 affects HCC progression. Firstly, PITPNA-AS1 was observed to be heightened in HCC tissues. Then function assays proved that overexpressing or silencing PITPNA-AS1 could manipulate the proliferation and motility of HCC cells. Besides, PITPNA-AS1 was located in the cytoplasm. Among the candidate miRNAs of PITPNA-AS1, miR-876-5p was an obvious target. Moreover, mechanism experiments validated that PITPNA-AS1 modulated WNT5A expression by targeting miR-876-5p. Rescue experiments affirmed that WNT5A silencing rescued the miR-876-5p suppression-induced cellular processes in PITPNA-AS1-silenced Hep3B cells. And in vivo experiments determined that PITPNA-AS1 regulated HCC progression in vivo via miR-876-5p/WNT5A pathway. In conclusion, this work shed lights on the modulatory mechanism of PITPNA-AS1/miR-876-5p/WNT5A axis in HCC, which might be pivotal for exploring effective diagnostic biomarkers and treatment strategies for HCC patients.

scholarly journals Upregulation of histamine receptor H1 promotes tumor progression and contributes to poor prognosis in hepatocellular carcinoma

Oncogene ◽  
2019 ◽  
Vol 39 (8) ◽  
pp. 1724-1738 ◽  
Author(s):  
Jing Zhao ◽  
Yiran Hou ◽  
Chun Yin ◽  
Jing Hu ◽  
Tian Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Histamine Receptor ◽  
Matrix Metalloproteinase 2 ◽  
Mice Model ◽  
Hcc Cells

AbstractH1 histamine receptor (H1HR) belongs to the family of rhodopsin-like G-protein-coupled receptors. Recent studies have shown that H1HR expression is increased in several types of cancer. However, its functional roles in tumor progression remain largely unknown, especially in hepatocellular carcinoma (HCC). We found that H1HR is frequently unregulated in HCC, which is significantly associated with both recurrence-free survival and overall survival in HCC patients. Functional experiments revealed that H1HR promoted both the growth and metastasis of HCC cells by inducing cell cycle progression, formation of lamellipodia, production of matrix metalloproteinase 2, and suppression of cell apoptosis. Activation of cyclic adenosine monophosphate-dependent protein kinase A was found to be involved in H1HR-mediated HCC cell growth and metastasis. In addition, we found that overexpression of H1HR was mainly due to the downregulation of miR-940 in HCC cells. Moreover, the H1HR inhibitor terfenadine significantly suppressed tumor growth and metastasis in an HCC xenograft nude mice model. Our findings demonstrate that H1HR plays a critical role in the growth and metastasis of HCC cells, which provides experimental evidence supporting H1HR as a potential drug target for the treatment of HCC.

scholarly journals Antitumor Effect of Lenvatinib Combined with Alisertib in Hepatocellular Carcinoma by Targeting the DNA Damage Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Jianwen Hao ◽  
Qizhen Peng ◽  
Keruo Wang ◽  
Ge Yu ◽  
Yi Pan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Anticancer Agents ◽  
Immunohistochemical Staining ◽  
Antitumor Effect ◽  
Combined Treatment ◽  
Single Agent ◽  
Xenograft Model ◽  
Cell Counting ◽  
Inhibition Of Proliferation

Background and Aim. Although a strong antitumor effect of lenvatinib has been noted for patients with unresectable hepatocellular carcinoma (HCC), its efficacy requires improvement. It is imperative to seek therapeutic strategies that combine Lenvatinib with other anticancer agents. In this study, we investigated the anticancer effect of combining lenvatinib with alisertib, aurora A kinase (AURKA) target drug, against HCC in vitro and in vivo. Methods. Immunohistochemical staining, sequencing, and genetic analysis of liver cancer tissues were performed. The antitumor efficacy of single-agent or combination treatment was measured by cell counting kit-8 assay and colony formation assays. Their antiproliferative and apoptosis activity is evaluated by cell cycle analyses and wound healing assays. The DNA-related proteins were also measured by Western blotting and immunohistochemical staining. The HepG2 xenograft model was used to detect the effects of lenvatinib-alisertib on the antitumor activity. Results. AURKA was found to be upregulated in HCC tissues (77.3%, 17/22). Combined alisertib and lenvatinib treatment significantly enhanced the inhibition of proliferation and migration in HepG2 and Hep3B cell lines compared to single-agent treatments (all P s < 0.01 ). Alisertib alone or in combination with lenvatinib demonstrated a significant increase in the percentage of super-G2 cells (lenvatinib 1 μM vs. lenvatinib 1 μM + alisertib 0.1 μM 8.84 ± 0.84 vs. 34.0 ± 1.54 , P < 0.001 ). Discontinuous spindles and missegregated chromosomes in HCC cells treated with alisertib in combination with lenvatinib were observed. We further revealed that combined treatment inhibited the expression of DNA damage pathway proteins compared to those of single-agent treatments. In nude mice, combined administration of alisertib combined with lenvatinib significantly enhanced the suppression of tumor growth and induced apoptosis (all P s < 0.01 ). Conclusions. Our findings provide evidence for the possible use of alisertib in combination with lenvatinib in the treatment of HCC for better therapeutic outcomes.

scholarly journals Parkin facilitates proteasome inhibitor-induced apoptosis via suppression of NF-κB activity in hepatocellular carcinoma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Xiaolan Zhang ◽  
Chun Lin ◽  
Junwei Song ◽  
Han Chen ◽  
Xuhong Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Protein Degradation ◽  
Anticancer Agents ◽  
Proteasome Inhibitor ◽  
Primary Liver Cancer ◽  
Proteasome Inhibitors ◽  
Apoptosis Resistance ◽  
Induced Apoptosis

Abstract The ubiquitin–proteasome system (UPS) is a tight homeostatic control mechanism of intracellular protein degradation and turnover involved in many human diseases. Proteasome inhibitors were initially developed as anticancer agents with potential benefits in the suppression of tumor growth. However, clinical trials of patients with solid tumors fail to demonstrate the same efficacy of these proteasome inhibitors. Here, we show that Parkin, an E3 ubiquitin ligase, is implicated in tumorigenesis and therapy resistance of hepatocellular carcinoma (HCC), the most common type of primary liver cancer in adults. Lower Parkin expression correlates with poor survival in patients with HCC. Ectopic Parkin expression enhances proteasome inhibitor-induced apoptosis and tumor suppression in HCC cells in vitro and in vivo. In contrast, knockdown of Parkin expression promotes apoptosis resistance and tumor growth. Mechanistically, Parkin promotes TNF receptor-associated factor (TRAF) 2 and TRAF6 degradation and thus facilitates nuclear factor-kappa-B (NF-κB) inhibition, which finally results in apoptosis. These findings reveal a direct molecular link between Parkin and protein degradation in the control of the NF-κB pathway and may provide a novel UPS-dependent strategy for the treatment of HCC by induction of apoptosis.

scholarly journals Induction of Apoptosis by Coptisine in Hep3B Hepatocellular Carcinoma Cells through Activation of the ROS-Mediated JNK Signaling Pathway

2020 ◽  
Vol 21 (15) ◽  
pp. 5502 ◽  
Author(s):  
So Young Kim ◽  
Hyun Hwangbo ◽  
Hyesook Lee ◽  
Cheol Park ◽  
Gi-Young Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Apoptotic Cell ◽  
Death Receptor ◽  
Jnk Signaling ◽  
Anticancer Efficacy ◽  
Bax Protein ◽  
Diagnosis Rate ◽  
Jnk Signaling Pathway ◽  
Hep3b Cells

Hepatocellular carcinoma (HCC) has a high mortality rate worldwide, and treatment is very limited due to its high recurrence and low diagnosis rate, and therefore there is an increasing need to develop more effective drugs to treat HCC. Coptisine is one of the isoquinoline alkaloids, and it has various pharmacological effects. However, the evidence for the molecular mechanism of the anticancer efficacy is still insufficient. Therefore, this study investigated the antiproliferative effect of coptisine on human HCC Hep3B cells and identified the action mechanism. Our results showed that coptisine markedly increased DNA damage and apoptotic cell death, which was associated with induction of death receptor proteins. Coptisine also significantly upregulated expression of proapoptotic Bax protein, downregulated expression of anti-apoptotic Bcl-2 protein, and activated caspase-3, -8, and -9. In addition, coptisine remarkably increased the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and release of cytochrome c into the cytoplasm. However, N-acetylcysteine (NAC), a ROS scavenger, significantly attenuated the apoptosis-inducing effect of coptisine. It is worth noting that coptisine significantly upregulated phosphorylation of ROS-dependent c-Jun N-terminal kinase (JNK), whereas treatment with JNK inhibitor could suppress an apoptosis-related series event. Taken together, our results suggest that coptisine has an anticancer effect in Hep3B cells through ROS-mediated activation of the JNK signaling pathway.

Sign in / Sign up

Export Citation Format

Share Document