ArticleAnnals of translational medicine2020
Blocking MAPK/ERK pathway sensitizes hepatocellular carcinoma cells to temozolomide via downregulating MGMT expression.
Article in Annals of translational medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 22 citations in OpenAlex.
- Effects of Fractionated Low Dose Ionizing Radiation on Cellular Senescence in Mouse Lung Tissue.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- The Role of miRNA-21 in the Metastasis of Hepatocellular Carcinoma as a Therapeutic Target.International journal of hematology-oncology and stem cell research · 2026Review
- Atorvastatin negatively regulates MAPK pathway in vitro to inhibit proliferation, migration, and invasion of hepatocellular carcinoma cells.Scientific reports · 2025Article
- Bergenin exerts anti-cancer activity in hepatocellular carcinoma via the PI3K/Akt/mTOR and MAPK/ERK pathways.Journal of molecular histology · 2025Article
- Temozolomide-Promoted MGMT Transcription Contributes to Chemoresistance by Activating the ERK Signalling Pathway in Malignant Melanoma.Journal of cellular and molecular medicine · 2025Article
- Revisiting Temozolomide's role in solid tumors: Old is gold?Journal of Cancer · 2024Review
- CD69 serves as a potential diagnostic and prognostic biomarker for hepatocellular carcinoma.Scientific reports · 2023Article
- Thymoquinone induces apoptosis in temozolomide-resistant glioblastoma cells via the p38 mitogen-activated protein kinase signaling pathway.Environmental toxicology · 2023Article
- The E3 ubiquitin ligase MG53 inhibits hepatocellular carcinoma by targeting RAC1 signaling.Oncogenesis · 2022Article
- Article
- Clinical Significance of TUBGCP4 Expression in Hepatocellular Carcinoma.Analytical cellular pathology (Amsterdam) · 2022Article
- Novel Methylation Biomarkers for Colorectal Cancer Prognosis.Biomolecules · 2021Review
- MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway.Journal of biomedical science · 2021Article
- CDC6 is a possible biomarker for hepatocellular carcinoma.International journal of clinical and experimental pathology · 2021Article
- m6A Modification-MediatedFrontiers in cell and developmental biology · 2021Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHepatocellular carcinoma (HCC) is the fourth most common malignant tumor in China. Temozolomide (TMZ) is a common chemotherapy drug which can effectively kill HCC cells in vitro. However, it is possible that HCC cells possess intrinsic resistance to TMZ. A key mechanism of TMZ resistance is the overexpression of O6-methylguanine-DNA methyltransferase (MGMT). Studies have shown that MAPK may be related to MGMT expression, U0126 is a highly selective inhibitor of MEK1 and MEK2, which were crucial molecule in cascade of mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) pathway. Sorafenib was another widely applicated target drug in HCC which could inhibit multiple kinases including MAPK/ERK. This research was aimed to investigate the efficacy of MAPK/ERK inhibitor U0126 and sorafenib combine with TMZ in the treatment of HCC.
methodsIn HCC cells, MAPK/ERK signaling pathway was blocked by U0126 and sorafenib. The effect of blocking MAPK/ERK signaling pathway on TMZ-induced cytotoxicity was evaluated by MTT assay, flow cytometry and TUNEL assay. DNA damage protein and the expression of MGMT were detected by Western-blot. After the downregulation of MAPK/ERK signaling pathway, MGMT mRNA expression and the protein expression of MGMT were quantified by quantitative real-time polymerase chain reaction (RT-qPCR) and immunofluorescence assay, respectively. HepG2 cells were transfected with an MGMT over expression plasmid. After transfection, the effect of U0126 on TMZ-induced cytotoxicity was evaluated by MTT and Western-Blot in MGMT OE cells. The influence of Sorafenib on TMZ-induced cytotoxicity to HCC cells was also detected by MTT assay.
resultsU0126 can enhance the chemosensitivity of HCC cells to TMZ. At the same time, we also found that U0126 increases the damage to DNA caused by TMZ in HepG2 cells. Moreover, the results from RT-qPCR and Western blot showed that U0126 downregulated MGMT mRNA and MGMT protein expression via blocking MAPK/ERK pathway. Furthermore, after transfection with an MGMT expression plasmid, overexpression of MGMT restored U0126-induced chemosensitivity to TMZ in HCC cells. Sorafenib can also increase the chemosensitivity of HCC cells to TMZ.
conclusionsOur studies suggest great clinical potential for the utilization of combined U0126 and TMZ in patients with advanced HCC.
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