scholarly journals The antitumour effect of galangin and luteolin with doxorubicin on chemically induced hepatocellular carcinoma in rats

2021 ◽  
Vol 25 (3) ◽  
pp. 174-184
Author(s):  
Gamal Atwa ◽  
Gamal Omran ◽  
Atef Abd Elbaky ◽  
Tarek Okda
Keyword(s):  
Hepatocellular Carcinoma ◽  
Antitumour Effect ◽  
Chemically Induced

EGF promotes DKK1 transcription in hepatocellular carcinoma by enhancing the phosphorylation and acetylation of histone H3

2020 ◽  
Vol 13 (657) ◽  
pp. eabb5727
Author(s):  
Jie Niu ◽  
Wei Li ◽  
Chao Liang ◽  
Xiao Wang ◽  
Xin Yao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nuclear Translocation ◽  
Histone H3 ◽  
Growth Factor Receptor ◽  
Transcript Level ◽  
Metastatic Progression ◽  
Chemically Induced ◽  
Epidermal Growth ◽  
Dual Inhibition ◽  
Dickkopf 1

The protein Dickkopf-1 (DKK1) is frequently overexpressed at the transcript level in hepatocellular carcinoma (HCC) and promotes metastatic progression through the induction of β-catenin, a Wnt signaling effector. We investigated how DKK1 expression is induced in HCC and found that activation of the epidermal growth factor receptor (EGFR) promoted parallel MEK-ERK and PI3K-Akt pathway signaling that converged to epigenetically stimulate DKK1 transcription. In HCC cell lines stimulated with EGF, EGFR-activated ERK phosphorylated the kinase PKM2 at Ser37, which promoted its nuclear translocation. Also in these cells, EGFR-activated Akt phosphorylated the acetyltransferase p300 at Ser1834. Subsequently, PKM2 and p300 mediated the phosphorylation and acetylation, respectively, of histone H3 at the DKK1 promoter, which synergistically enhanced DKK1 transcription. The mechanism was supported with mutational analyses in cells and in a chemically induced HCC model in rats. The findings suggest that dual inhibition of the MEK and PI3K pathways might suppress the expression of DKK1 and, consequently, tumor metastasis in patients with HCC.

ApoE-modified liposomes mediate the antitumour effect of survivin promoter-driven HSVtk in hepatocellular carcinoma

2019 ◽  
Vol 27 (10-11) ◽  
pp. 754-767
Author(s):  
Xiuli Mu ◽  
Xi Wang ◽  
Yan Wei ◽  
Chaochao Wen ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Antitumour Effect ◽  
Survivin Promoter

scholarly journals A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Torsten Diesinger ◽  
Alfred Lautwein ◽  
Sebastian Bergler ◽  
Dominik Buckert ◽  
Christian Renz ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Chorioallantoic Membrane ◽  
Simultaneous Increase ◽  
Dependent Manner ◽  
Antitumour Effect ◽  
Proliferating Cells ◽  
Nonalcoholic Fatty Liver ◽  
Cycle Regulation ◽  
First Time

Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD.

HP33: hepatocellular carcinoma-enriched 33-kDa protein with similarity to mitochondrial N-acyltransferase but localized in a microtubule-dependent manner at the centrosome

1999 ◽  
Vol 112 (9) ◽  
pp. 1353-1364
Author(s):  
T. Nakadai ◽  
T. Kishimoto ◽  
Y. Miyazawa ◽  
N. Okada ◽  
Y. Makino ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Staining Pattern ◽  
Hepatocyte Proliferation ◽  
Dependent Manner ◽  
Hepatic Cells ◽  
Chemically Induced ◽  
Its Gene ◽  
Liver And Kidney ◽  
Mitochondrial Staining

Using a new subtraction method and chemically induced rat hepatocellular carcinomas, we identified a hepatocellular carcinogenesis and hepatocyte proliferation-related gene designated hp33 that encoded a 33-kDa protein. The predicted protein was similar to the bovine aralkyl N-acyltransferase and arylacetyl N-acyltransferase. HP33 was restrictively expressed in the liver and kidney, and its gene expression was stimulated in the regenerating liver as well as in hepatocellular carcinoma. Interestingly, it was demonstrated in various hepatic cells that HP33 was localized in regions surrounding the centrosome, where mitochondria were not concentrated. Moreover, its centrosomal localization was evident in the interphase but not in the mitotic phase of the cell cycle. The centrosomal localization of HP33 was dependent on microtubules, and ectopically expressed HP33 was seen at centrosomes even in fibroblasts, which do not exhibit a typical staining pattern of HP33. The centrosomal localization of HP33 became invisible by nocodazole treatment, whereas the mitochondrial staining pattern was not affected by it. In vitro cosedimentation experiments using purified microtubules indicated that HP33 bound to MTs directly and that its MT-binding ability was dependent on the C-terminal basic domain of the protein. These results suggest that, different from early predictions based on its primary structure, HP33 has a growth- and carcinogenesis-related function that may be independent of mitochondrial function.

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