ArticleMolecular oncology2019
Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib.
Article in Molecular oncology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 39 citations in OpenAlex.
- Cancer stem cells: advances in the glucose, lipid and amino acid metabolism.Molecular and cellular biochemistry · 2024Review
- Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin.International journal of molecular sciences · 2024Review
- A Novel Combinatorial Regimen Using Sorafenib and Uttroside B, A US FDA-designated 'Orphan Drug', for the Treatment of Hepatocellular Carcinoma.Anti-cancer agents in medicinal chemistry · 2024Article
- The potential anti-tumor effect of anesthetics on cancer by regulating autophagy.Frontiers in pharmacology · 2024Review
- NANOG regulates epithelial-mesenchymal transition via AMPK/mTOR signalling pathway in ovarian cancer SKOV-3 and A2780 cells.Journal of cellular and molecular medicine · 2022Article
- Article
- The Natural Chemotherapeutic Capsaicin Activates AMPK through LKB1 Kinase and TRPV1 Receptors in Prostate Cancer Cells.Pharmaceutics · 2022Article
- Role of CD36 in cancer progression, stemness, and targeting.Frontiers in cell and developmental biology · 2022Review
- Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway.Journal of experimental & clinical cancer research : CR · 2021Article
- Metformin exerts anti-AR-negative prostate cancer activity via AMPK/autophagy signaling pathway.Cancer cell international · 2021Article
- Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells.World journal of stem cells · 2021Review
- Effect of the Hypoxia Inducible Factor on Sorafenib Resistance of Hepatocellular Carcinoma.Frontiers in oncology · 2021Review
- AMP-Activated Protein Kinase: Do We Need Activators or Inhibitors to Treat or Prevent Cancer?International journal of molecular sciences · 2020Review
- Propofol activates AMPK to inhibit the growth of HepG2 cellsJournal of gastrointestinal oncology · 2020Article
- Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity.Cancers · 2020Review
- Dysregulated lipid metabolism in hepatocellular carcinoma cancer stem cells.Molecular biology reports · 2020Article
- NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway.Cell death & disease · 2020Article
- IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells.OncoTargets and therapy · 2020Article
- Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect.Cancer management and research · 2020Review
- The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma.EBioMedicine · 2020Review
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells (CSCs) that self-renew and often escape therapy. The key metabolic sensor AMP-activated kinase (AMPK) has recently been recognized as a tumour growth regulator. In this study, we aimed to elucidate the role of AMPK in the development of a stem cell phenotype in HCC cells. To this end, we enriched the CSC population in HCC cell lines that showed increased expression of drug resistance (ALDH1A1, ABCB1A) and stem cell (CD133, Nanog, Oct4, alpha fetoprotein) markers and demonstrated their stemness phenotype. These cells were refractory to sorafenib-induced cell death. We report that sorafenib-resistant cells had lower levels of total and phosphorylated AMPK as well as its downstream substrate, ACC, compared with the parental cells. Interestingly, AMPK knockdown with siRNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib-induced cell death. Conversely, the upregulation of AMPK, either by transfection or by pharmacological activation with A-769662, decreased the expression of ALDH1A1, ABCB1A, CD133, Nanog, Oct4, and alpha fetoprotein, and restored sensitivity to sorafenib. Analysis of the underlying mechanism points to hypoxia-inducible factor HIF-1α as a regulator of stemness. In vivo studies in a xenograft mouse model demonstrated that stem-like cells have greater tumourigenic capacity. AMPK activation reduced xenograft tumour growth and decreased the expression of stem cell markers. Taken together, these results indicate that AMPK may serve as a novel target to overcome chemoresistance in HCC.
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