ArticleTumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine2016
MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK.
Article in Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 11 citations in OpenAlex.
- CCDC137 affects sorafenib resistance in hepatocellular carcinoma cells by activating the AKT/mTOR signaling pathway.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Article
- Post-translational modification in hepatocellular carcinoma resistance: molecular mechanisms and therapeutic targeting.Frontiers in immunology · 2026Review
- PFDN6L Gene Predicts Good Prognosis Associated with Its Inhibition of the Stem-Ness Properties in Hepatocellular Carcinoma.Oncology research · 2025Article
- NEAT1-SOD2 Axis Confers Sorafenib and Lenvatinib Resistance by Activating AKT in Liver Cancer Cell Lines.Current issues in molecular biology · 2023Article
- Phenformin synergistically sensitizes liver cancer cells to sorafenib by downregulating CRAF/ERK and PI3K/AKT/mTOR pathways.American journal of translational research · 2021Article
- Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity.Cancers · 2020Review
- Ataxia telangiectasia mutated pathway disruption affects hepatic DNA and tissue damage in nonalcoholic fatty liver disease.Experimental and molecular pathology · 2020Article
- Mitotic quiescence in hepatic cancer stem cells: An incognito mode.Oncology reviews · 2020Article
- Targeting liver cancer stem cells for the treatment of hepatocellular carcinoma.Therapeutic advances in gastroenterology · 2019Review
- Interaction between CD133 and PI3K-p85 promotes chemoresistance in gastric cancer cells.American journal of translational research · 2018Article
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10 authors at 1 institution in 1 country.
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Abstract
Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib.
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