ArticleCell death & disease2020
Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 67 citations in OpenAlex.
- 1D228 Attenuates Sorafenib Resistance in Renal Cell Carcinoma Models by Dual Targeting c-Met and AXL.Cells · 2026Article
- Understanding how hypoxia contributes to liver cancer stem cells maintenance.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Multidimensional Regulatory Network and Spatiotemporal Specificity of FOXO Transcription Factors in Digestive System Tumors: Recent Advances.International journal of molecular sciences · 2026Review
- Artesunate nanoliposomes in hepatocellular carcinoma: mechanistic ferroptosis induction and translational opportunities.Discover oncology · 2026Review
- GRB2 Promotes Sorafenib Resistance in Hepatocellular Carcinoma Cells Under Hypoxia by Activating the PI3K/AKT Signaling Pathway.Journal of hepatocellular carcinoma · 2026Article
- Review
- Curcumin controls the senescence of adipose-derived mesenchymal stem cells via the FoxO3/autophagy signaling pathway to enhance joint homeostasis for osteoarthritis therapy.Stem cell research & therapy · 2025Article
- The Biological Role and Clinical Significance of BECLIN-1 in Cancer.International journal of molecular sciences · 2025Review
- A microfluidic tumor-on-chip platform deciphers hypoxia-driven FOXO3a/PD-L1 signaling in gastric cancer immunotherapy resistance.Materials today. Bio · 2025Article
- Exploring the Molecular Mechanism of 1,25(OH)Current issues in molecular biology · 2025Article
- Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance.Journal of hematology & oncology · 2025Review
- Homotypic cell membrane-camouflaged biomimetic PLGA nanoparticle loading triptolide for the treatment of hepatocellular carcinoma.Drug delivery · 2024Article
- Hemoglobin nanoclusters-mediated regulation of KPNA4 in hypoxic tumor microenvironment enhances photodynamic therapy in hepatocellular carcinoma.Journal of nanobiotechnology · 2024Article
- Hypoxia-Inducible Factor-Dependent and Independent Mechanisms Underlying Chemoresistance of Hypoxic Cancer Cells.Cancers · 2024Review
- Article
- New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma-Today and Tomorrow.International journal of molecular sciences · 2024Review
- Transcriptional dysregulation of autophagy in the muscle of a mouse model of Duchenne muscular dystrophy.Scientific reports · 2024Article
- The Impact of Statins on the Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib or Lenvatinib.Cancers · 2024Article
- Shikonin Induces Autophagy and Apoptosis in Esophageal Cancer EC9706 Cells by Regulating the AMPK/mTOR/ULK Axis.Analytical cellular pathology (Amsterdam) · 2024Article
- Active Autophagy Is Associated with Favorable Outcome in Patients with Surgically Resected Cholangiocarcinoma.Cancers · 2023Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sorafenib, a multikinase inhibitor, is considered as the only approved drug to cure the advanced hepatocellular carcinoma (HCC); however, the acquired chemoresistance caused by intratumoral hypoxia through sorafenib long term therapy induces sorafenib inefficacy. We demonstrated here that hypoxia significantly attenuated sensitivity of HCC cells to sorafenib treatment and reduced its proliferation. Autophagy was observed in sorafenib-treated HCC cells in hypoxia, and inhibition of autophagy by 3-MA eliminated hypoxia-induced sorafenib resistance. Further study revealed hypoxia-activated FOXO3a, an important cellular stress transcriptional factor, via inducing its dephosphorylation and nuclear location; and FOXO3a-dependent transcriptive activation of beclin-1 was responsible for hypoxia-induced autophagy in HCC cells. Knockout of FOXO3a inhibited the autophagy induced by sorafenib itself in normoxia and significantly enhanced the cytotoxicity of sorafenib in HCC cells; and it also inhibited the hypoxia-induced autophagy and achieved the same effect in sorafenib sensitivity-enhancement in HCC cells as it in normoxia. Finally, knockout of intratumoral FOXO3a significantly enhanced curative efficacy of sorafenib via inhibition of autophagy in xenograft tumors in nude mice. Collectively, our study suggests that FOXO3a plays a key role in regulating hypoxia-induced autophagy in sorafenib-treated HCC, and FOXO3-targeted therapy may serve as a promising approach to improve clinical prognosis of patients suffering from HCC.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.