ArticlePloS one2017
Activation of phosphatidylinositol 3-kinase/AKT/snail signaling pathway contributes to epithelial-mesenchymal transition-induced multi-drug resistance to sorafenib in hepatocellular carcinoma cells.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 109 citations in OpenAlex.
- Concurrent Inhibition of AKT and GLUT1 Reveals Endpoint-Specific Effects on Glucose Metabolism and Cell Death in HepG2 Hepatocyte-Derived Cells.Biomedicines · 2026Article
- Decoding the Snail transcriptional network: its role in cancer progression and therapy.Biology direct · 2026Review
- LAC-TME classifier: machine learning-driven model predicts survival and prioritizes targeted therapy in clear cell renal cell carcinoma.Journal of cancer research and clinical oncology · 2025Article
- Pentagamavunone-1 targets excessive MYCN/NCYM expression mediated by mitotic arrest to suppress hepatocellular carcinoma proliferation.Cancer gene therapy · 2025Article
- Unveiling EFNB2 as a Key Player in Sorafenib Resistance: Insights from Bioinformatics Analysis and Functional Validation in Hepatocellular Carcinoma.Biochemical genetics · 2025Article
- Article
- Galectins and Liver Diseases.International journal of molecular sciences · 2025Review
- Enhanced inhibitory effects of mianserin in combination with sorafenib on liver cancer growth through targeting the CCR9-AKT pathway.American journal of cancer research · 2025Article
- LncRNA PTENP1/miR-21/PTEN Axis Modulates EMT and Drug Resistance in Cancer: Dynamic Boolean Modeling for Cell Fates in DNA Damage Response.International journal of molecular sciences · 2024Article
- Article
- The Combination of Sorafenib and PGV-1 Inhibits the Proliferation of Hepatocellular Carcinoma Through c-Myc Suppression in an Additive Manner: In Vitro Studies.Advances in pharmacological and pharmaceutical sciences · 2024Article
- Roles of clinical application of lenvatinib and its resistance mechanism in advanced hepatocellular carcinoma (Review).American journal of cancer research · 2024Review
- In Silico Analysis of MicroRNA Expression Data in Liver Cancer.Cancer informatics · 2023Article
- The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products.Antioxidants (Basel, Switzerland) · 2022Review
- Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma.Cell death & disease · 2022Article
- Sirtuins and Hypoxia in EMT Control.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Predicting Genomic Alterations of Phosphatidylinositol-3 Kinase Signaling in Hepatocellular Carcinoma: A Radiogenomics Study Based on Next-Generation Sequencing and Contrast-Enhanced CT.Annals of surgical oncology · 2022Article
- Article
- Link of sorafenib resistance with the tumor microenvironment in hepatocellular carcinoma: Mechanistic insights.Frontiers in pharmacology · 2022Review
- Noncoding RNAs in pyroptosis and cancer progression: Effect, mechanism, and clinical application.Frontiers in immunology · 2022Review
5 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sorafenib, an orally available kinase inhibitor, is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), and it exerts potent inhibitory activity against epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR) by inhibiting mitogen-activated protein kinase (MAPK) signaling in HCC. However, after long-term exposure to sorafenib, HCC cells exhibit EMT and resistance to sorafenib. The activation of AKT by sorafenib is thought to be responsible for the development of these characteristics. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance and the progression to EMT. Sorafenib-resistant cells showed increased metastatic and invasive ability, with a higher expression of P-glycoprotein (P-gp), compared with the parental cells. This phenomenon was at least partially due to EMT and the appearance of MDR in sorafenib-resistant HCC cells. Moreover, MDR was a downstream molecular event of EMT. Silencing Snail with siRNA blocked EMT and partially reversed the MDR, thereby markedly abolishing invasion and metastasis in sorafenib-resistant HCC cells, but silencing of MDR1 had no effect on the EMT phenotype. Additionally, HCC parental cells that were stably transfected with pCDNA3.1-Snail exhibited EMT and MDR. Two sorafenib-resistant HCC cell lines, established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to MK-2206, a novel allosteric AKT inhibitor. Thus, the combination of sorafenib and MK-2206 led to significant reversion of the EMT phenotype and P-gp-mediated MDR by downregulating phosphorylated AKT. These findings underscore the significance of EMT, MDR and enhanced PI3K/AKT signaling in sorafenib-resistant HCC cells.
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