scholarly journals Ursolic Acid Suppresses Cholesterol Biosynthesis and Exerts Anti-Cancer Effects in Hepatocellular Carcinoma Cells

2019 ◽  
Vol 20 (19) ◽  
pp. 4767 ◽  
Author(s):  
Geon-Hee Kim ◽  
Sang-Yeon Kan ◽  
Hyeji Kang ◽  
Sujin Lee ◽  
Hyun Myung Ko ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chronic Diseases ◽  
Ursolic Acid ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Lowering ◽  
Anti Cancer ◽  
Sterol Regulatory Element ◽  
Cholesterol Supplementation ◽  
Hcc Cells

Abnormally upregulated cholesterol and lipid metabolism, observed commonly in multiple cancer types, contributes to cancer development and progression through the activation of oncogenic growth signaling pathways. Although accumulating evidence has shown the preventive and therapeutic benefits of cholesterol-lowering drugs for cancer management, the development of cholesterol-lowering drugs is needed for treatment of cancer as well as metabolism-related chronic diseases. Ursolic acid (UA), a natural pentacyclic terpenoid, suppresses cancer growth and metastasis, but the precise underlying molecular mechanism for its anti-cancer effects is poorly understood. Here, using sterol regulatory element (SRE)-luciferase assay-based screening on a library of 502 natural compounds, this study found that UA activates sterol regulatory element-binding protein 2 (SREBP2). The expression of cholesterol biosynthesis-related genes and enzymes increased in UA-treated hepatocellular carcinoma (HCC) cells. The UA increased cell cycle arrest and apoptotic death in HCC cells and reduced the activation of oncogenic growth signaling factors, all of which was significantly reversed by cholesterol supplementation. As cholesterol supplementation successfully reversed UA-induced attenuation of growth in HCC cells, it indicated that UA suppresses HCC cells growth through its cholesterol-lowering effect. Overall, these results suggested that UA is a promising cholesterol-lowering nutraceutical for the prevention and treatment of patients with HCC and cholesterol-related chronic diseases.

scholarly journals Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism

2018 ◽  
Vol 19 (10) ◽  
pp. 3127 ◽  
Author(s):  
Young-Seon Kim ◽  
Yoon-Mi Lee ◽  
Taek-In Oh ◽  
Dong Shin ◽  
Geon-Hee Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cholesterol Metabolism ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Akt Signaling ◽  
Chinese Herbs ◽  
Advanced Hepatocellular Carcinoma ◽  
Multikinase Inhibitor ◽  
Anti Cancer ◽  
Sensitizing Effect

Reduced therapeutic efficacy of sorafenib, a first-generation multikinase inhibitor, is often observed during the treatment of advanced hepatocellular carcinoma (HCC). Emodin is an active component of Chinese herbs, and is effective against leukemia, lung cancer, colon cancer, pancreatic cancer, and HCC; however, the sensitizing effect of emodin on sorafenib-based HCC therapy has not been evaluated. Here, we demonstrate that emodin significantly improved the anti-cancer effect of sorafenib in HCC cells, such as HepG2, Hep3B, Huh7, SK-HEP-1, and PLC/PRF5. Mechanistically, emodin inhibits sterol regulatory element-binding protein-2 (SREBP-2) transcriptional activity, which suppresses cholesterol biosynthesis and oncogenic protein kinase B (AKT) signaling. Additionally, attenuated cholesterol synthesis and oncogenic AKT signaling inactivated signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. Furthermore, emodin synergistically increased cell cycle arrest in the G1 phase and apoptotic cells in the presence of sorafenib. Animal models xenografted with HepG2 or SK-HEP-1 cells also showed that the combination of emodin and sorafenib was sufficient to inhibit tumor growth. Overall, these results suggested that the combination of emodin and sorafenib may offer a potential therapy for patients with advanced HCC.

scholarly journals Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1

2021 ◽  
Vol 12 ◽  
Author(s):  
Cancan Zheng ◽  
Yidong Zhu ◽  
Qinwen Liu ◽  
Tingting Luo ◽  
Wenwen Xu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Antitumor Effects ◽  
Element Binding Protein ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death and has a poor prognosis worldwide, thus, more effective drugs are urgently needed. In this article, a small molecule drug library composed of 1,056 approved medicines from the FDA was used to screen for anticancer drugs. The tetracyclic compound maprotiline, a highly selective noradrenergic reuptake blocker, has strong antidepressant efficacy. However, the anticancer effect of maprotiline remains unclear. Here, we investigated the anticancer potential of maprotiline in the HCC cell lines Huh7 and HepG2. We found that maprotiline not only significantly restrained cell proliferation, colony formation and metastasis in vitro but also exerted antitumor effects in vivo. In addition to the antitumor effect alone, maprotiline could also enhance the sensitivity of HCC cells to sorafenib. The depth studies revealed that maprotiline substantially decreased the phosphorylation of sterol regulatory element-binding protein 2 (SREBP2) through the ERK signaling pathway, which resulted in decreased cholesterol biosynthesis and eventually impeded HCC cell growth. Furthermore, we identified cellular retinoic acid binding protein 1 (CRABP1) as a direct target of maprotiline. In conclusion, our study provided the first evidence showing that maprotiline could attenuate cholesterol biosynthesis to inhibit the proliferation and metastasis of HCC cells through the ERK-SREBP2 signaling pathway by directly binding to CRABP1, which supports the strategy of repurposing maprotiline in the treatment of HCC.

scholarly journals Wnt signaling mediates oncogenic synergy between Akt and Dlx5 in T-cell lymphomagenesis by enhancing cholesterol synthesis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yinfei Tan ◽  
Eleonora Sementino ◽  
Zemin Liu ◽  
Kathy Q. Cai ◽  
Joseph R. Testa
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Cholesterol Synthesis ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Homeobox Gene ◽  
Rna Seq ◽  
Expression Of Genes ◽  
Highly Sensitive ◽  
Sterol Regulatory Element

Abstract The Dlx5 homeobox gene was first implicated as an oncogene in a T-ALL mouse model expressing myristoylated (Myr) Akt2. Furthermore, overexpression of Dlx5 was sufficient to drive T-ALL in mice by directly activating Akt and Notch signaling. These findings implied that Akt2 cooperates with Dlx5 in T-cell lymphomagenesis. To test this hypothesis, Lck-Dlx5;Lck-MyrAkt2 transgenic mice were generated. MyrAkt2 synergized with Dlx5 to greatly accelerate and enhance the dissemination of T-lymphomagenesis. RNA-seq analysis performed on lymphomas from Lck-Dlx5;Lck-MyrAkt mice revealed upregulation of genes involved in the Wnt and cholesterol biosynthesis pathways. Combined RNA-seq and ChIP-seq analysis of lymphomas from Lck-Dlx5;Lck-MyrAkt mice demonstrated that β-catenin directly regulates genes involved in sterol regulatory element binding transcription factor 2 (Srebf2)-cholesterol synthesis. These lymphoma cells had high Lef1 levels and were highly sensitive to β-catenin and Srebf2-cholesterol synthesis inhibitors. Similarly, human T-ALL cell lines with activated NOTCH and AKT and elevated LEF1 levels were sensitive to inhibition of β-catenin and cholesterol pathways. Furthermore, LEF1 expression positively correlated with expression of genes involved in the cholesterol synthesis pathway in primary human T-ALL specimens. Together, these data suggest that targeting β-catenin and/or cholesterol biosynthesis, together with AKT, could have therapeutic efficacy in a subset of T-ALL patients.

scholarly journals SREBP2 delivery to striatal astrocytes normalizes transcription of cholesterol biosynthesis genes and ameliorates pathological features in Huntington’s Disease

2020 ◽  
Author(s):  
Giulia Birolini ◽  
Gianluca Verlengia ◽  
Francesca Talpo ◽  
Claudia Maniezzi ◽  
Lorena Zentilin ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Nuclear Translocation ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Biosynthesis Pathway ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Cholesterol Biosynthesis Pathway

AbstractBrain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntington’s Disease (HD). One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP-controlled genes in the cholesterol biosynthesis pathway.Here we evaluated the efficacy of a gene therapy based on the unilateral intra-striatal injection of a recombinant adeno-associated virus 2/5 (AAV2/5) targeting astrocytes specifically and carrying the N-terminal fragment of human SREBP2 (hSREBP2).Robust hSREBP2 expression in striatal glial cells in HD mice activated the transcription of cholesterol biosynthesis pathway genes, restored synaptic transmission, reversed Drd2 transcript levels decline, cleared muHTT aggregates and attenuated behavioral deficits. We conclude that glial SREBP2 participates in HD brain pathogenesis in vivo and that AAV-based delivery of SREBP2 to astrocytes counteracts key features of HD.

scholarly journals Quercetin 3-Glucoside Protects Neuroblastoma (SH-SY5Y) Cellsin Vitroagainst Oxidative Damage by Inducing Sterol Regulatory Element-binding Protein-2-mediated Cholesterol Biosynthesis

2007 ◽  
Vol 283 (4) ◽  
pp. 2231-2245 ◽  
Author(s):  
Ramani Soundararajan ◽  
Alexander D. Wishart ◽  
H. P. Vasantha Rupasinghe ◽  
Mayi Arcellana-Panlilio ◽  
Carolanne M. Nelson ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

scholarly journals MicroRNA-936 Targets JAG1 and Inhibits the Proliferation of Hepatocellular Carcinoma Cells

2021 ◽  
Vol 20 ◽  
pp. 153303382098578
Author(s):  
Junmei Tian ◽  
Yongfei Zhao ◽  
Li Li ◽  
Yanling Cui ◽  
Yang Wu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cancer Progression ◽  
Malignant Tumors ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Functional Study ◽  
Functional Roles ◽  
Anti Cancer ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Investigating the underlying molecular mechanism is essential for the treatment and prognosis of HCC. Emerging evidence suggests that microRNAs (miRNAs) play pivotal roles in cancer progression. Down-regulation of miR-936 has been found in several cancers, which serves as a tumor suppressor to inhibit the development of cancers. However, the clinical significance and functional roles of miR-936 in HCC have not been determined. To explore this, the expression of miR-936 in HCC tissues and cells was detected by RT-qPCR. Cell Counting Kit-8 (CCK-8) assay, cell migration and cell cycle analysis were performed to evaluate the effects of miR-936 on the growth of HCC cells. The targets of miR-936 were predicted using the miRDB database and confirmed by luciferase reporter experiments. The protein expression of targets was determined by western blot. The results showed that miR-936 was significantly decreased in HCC tissues and cell lines. Low expression of miR-936 was associated with the advance progression and poor survival of HCC patients (P = 0.0036). Functional study revealed that overexpression of miR-936 inhibited the proliferation, migration (decreased to ∼0.26 fold) and induced cell cycle arrested in G1 phase (from 35.3% to 44.7%) of HCC cells. Additionally, miR-936 targeted the 3′-untranslated region (UTR) of jagged-1 (JAG1) and reduced the expression of JAG1 (decreased to ∼0.35 fold). JAG1 was found to be up-regulated in HCC tissues and was inversely correlated with the expression of miR-936 (Pearson r = −0.4633; P = 0.0007). The anti-cancer effects of miR-936 on the proliferation of HCC cells were partially reversed by the rescue of JAG1. Therefore, these results suggested that miR-936 might be a potential target for HCC treatment.

scholarly journals Upregulation of PD-L1 expression promotes epithelial-to-mesenchymal transition in sorafenib-resistant hepatocellular carcinoma cells

2020 ◽  
Vol 8 (5) ◽  
pp. 390-398
Author(s):  
Gui-Li Xu ◽  
Cai-Fang Ni ◽  
Han-Si Liang ◽  
Yun-Hua Xu ◽  
Wan-Sheng Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Regulatory Element ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Knock Down ◽  
Huh7 Cells ◽  
Element Binding Protein ◽  
Hcc Cells ◽  
E Cadherin

Abstract Background The epithelial-to-mesenchymal transition (EMT) status is associated with programmed death-1 ligand 1 (PD-L1) expression in various cancers. However, the role and molecular mechanism of PD-L1 in the EMT of sorafenib-resistant hepatocellular carcinoma (HCC) cells remain elusive. In this study, we aimed to investigate the regulation of PD-L1 on the EMT in sorafenib-resistant HCC cells. Methods Initially, the sorafenib-resistant HCC cell lines HepG2 SR and Huh7 SR were established. Western-blot assays were used to detect the expression of PD-L1, E-cadherin, and N-cadherin. The intervention and overexpression of PD-L1 were used to explore the role of PD-L1 in the regulation of EMT in HepG2 SR and Huh7 SR cells. Cell migration and invasion were assessed by transwell assays. PD-L1 or Sterol regulatory element-binding protein 1 (SREBP-1) overexpression and knock-down were performed in order to study the mechanism of PD-L1 in sorafenib-resistant HCC cells. Results PD-L1 expression was upregulated, whereas E-cadherin levels were downregulated and N-cadherin expression was increased in HepG2 SR and Huh7 SR cells. The cell viabilities of HepG2 and Huh7 cells were lower than those of HepG2 SR and Huh7 SR cells. PD-L1 overexpression reduced E-cadherin expression and increased N-cadherin levels, whereas PD-L1 knock-down increased E-cadherin expression and decreased N-cadherin expression. PD-L1 expression promoted EMT and the migratory and invasive abilities of HepG2 SR and Huh7 SR cells. PD-L1 promoted the EMT of sorafenib-resistant HCC cells via the PI3K/Akt pathway by activating SREBP-1 expression in HepG2 SR and Huh7 SR cells. Conclusions The findings reveal that PD-L1 expression promotes EMT of sorafenib-resistant HCC cells.

scholarly journals LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells

2020 ◽  
Author(s):  
Yongfang Ma ◽  
Ruyue Xu ◽  
Xueke Liu ◽  
Yinci Zhang ◽  
Li Song ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Combined Treatment ◽  
Acquired Resistance ◽  
Cycle Progression ◽  
Acquired Drug Resistance ◽  
Anti Cancer ◽  
Apoptotic Effects ◽  
Hcc Cells

Abstract Background: Due to the reactivation of ERK signaling in sorafenib-resisitant hepatocellular carcinoma (HCC) cells, in this study, the anti-cancer effect of LY3214996 (selective ERK1/2 inhibitor) combined with sorafenib on HCC cells was evaluated. Methods: Phosphorylation of the key kinases in the Ras/Raf/MAPK and PI3K/Akt pathways were detected using Western blot. Cells proliferation, migration, cell cycle and apoptosis were evaluated in Huh7 and Huh7 R cells. Results: LY3214996 significantly reduced phosphorylation levels of the tested kinases of Ras/Raf/MAPK and PI3K/Akt pathways including p-c-Raf, p-P90RSK, p-S6K and p-eIF4EBP1 activated by sorafenib, despite increased p-ERK1/2 levels. It was found that LY3214996 enhanced the anti-proliferation, anti-migration, blocking cell cycle progression and pro-apoptotic effects of sorafenib on Huh7 R cells. Conclusions: The reactivation of ERK1/2 might be highly related to molecular mechanism of acquired drug resistance. LY3214996 combined with sorafenib enhanced anti-tumor effects in HCC. Consequently, combined treatment of LY3214996 and sorafenib provides a second-line therapy for acquired resistant in advanced HCC.

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