ArticleAutophagy2014
Q6, a novel hypoxia-targeted drug, regulates hypoxia-inducible factor signaling via an autophagy-dependent mechanism in hepatocellular carcinoma.
Article in Autophagy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.The Journal of cell biology · 2025Article
- Navigating liver cancer: Precision targeting for enhanced treatment outcomes.Drug delivery and translational research · 2025Review
- For and against tumor microenvironment: Nanoparticle-based strategies for active cancer therapy.Materials today. Bio · 2025Review
- Hemoglobin nanoclusters-mediated regulation of KPNA4 in hypoxic tumor microenvironment enhances photodynamic therapy in hepatocellular carcinoma.Journal of nanobiotechnology · 2024Article
- Revisiting the role of hypoxia-inducible factors and nuclear factor erythroid 2-related factor 2 in regulating macrophage inflammation and metabolism.Frontiers in cellular and infection microbiology · 2024Review
- Myo1b promotes tumor progression and angiogenesis by inhibiting autophagic degradation of HIF-1α in colorectal cancer.Cell death & disease · 2022Article
- Differential molecular mechanistic behavior of HDACs in cancer progression.Medical oncology (Northwood, London, England) · 2022Review
- Autophagic degradation of CCN2 (cellular communication network factor 2) causes cardiotoxicity of sunitinib.Autophagy · 2022Article
- Immunoautophagy-Related Long Noncoding RNA (IAR-lncRNA) Signature Predicts Survival in Hepatocellular Carcinoma.Biology · 2021Article
- MiR-375 Impairs the Invasive Capabilities of Hepatoma Cells by Targeting HIF1α Under Hypoxia.Digestive diseases and sciences · 2021Article
- The competitive endogenous RNA regulatory network reveals potential prognostic biomarkers for overall survival in hepatocellular carcinoma.Cancer science · 2019Article
- Hypoxia-targeted drug delivery.Chemical Society reviews · 2019Review
- Chloramphenicol Induces Autophagy and Inhibits the Hypoxia Inducible Factor-1 Alpha Pathway in Non-Small Cell Lung Cancer Cells.International journal of molecular sciences · 2019Article
- Autophagy Suppresses Invasiveness of Endometrial Cells through Reduction of Fascin-1.BioMed research international · 2018Article
- Hypoxia inducible factors in hepatocellular carcinoma.Oncotarget · 2017Review
- Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Review
- Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1.British journal of cancer · 2017Article
- lncRNA NBR2 modulates cancer cell sensitivity to phenformin through GLUT1.Cell cycle (Georgetown, Tex.) · 2016Article
- Cabazitaxel-induced autophagy via the PI3K/Akt/mTOR pathway contributes to A549 cell death.Molecular medicine reports · 2016Article
- Autophagy degrades hypoxia inducible factors.Molecular & cellular oncology · 2016Article
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tumor hypoxia underlies treatment failure and yields more aggressive and metastatic cancer phenotypes. Although therapeutically targeting these hypoxic environments has been proposed for many years, to date no approaches have shown the therapeutic value to gain regulatory approval. Here, we demonstrated that a novel hypoxia-activated prodrug, Q6, exhibits potent antiproliferative efficacy under hypoxic conditions and induces caspase-dependent apoptosis in 2 hepatocellular carcinoma (HCC) cell lines, with no obvious toxicity being detected in 2 normal liver cell lines. Treatment with Q6 markedly downregulated HIF1A [hypoxia inducible factor 1, α subunit (basic helix-loop-helix transcription factor)] expression and transcription of the downstream target gene, VEGFA (vascular endothelial growth factor A). This dual hypoxia-targeted modulation mechanism leads to high potency in suppressing tumor growth and vascularization in 2 in vivo models. Intriguingly, it is the autophagy-dependent degradation pathway that plays a crucial role in Q6-induced attenuation of HIF1A expression, rather than the proteasome-dependent pathway, which is normally regarded as the predominant mechanism underlying posttranslational regulation of HIF1A. Inhibition of autophagy, either by short interfering RNA (siRNA) or by chemical inhibitors, blocked Q6-induced HIF1A degradation. Autophagic degradation of HIF1A was further confirmed by the observation that HIF1A coimmunoprecipitated with the ubiquitin-binding adaptor protein, SQSTM1, which is degraded through autophagy. Additionally, silencing of SQSTM1 inhibited Q6-induced HIF1A degradation. These findings suggest that the novel hypoxia-targeted agent, Q6, has potential clinical value in the therapy of HCC. Furthermore, the identification of autophagy as a crucial regulator of HIF1A provides new insights into hypoxia-related treatments.
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