ArticleCancer discovery2023
Targeting UGCG Overcomes Resistance to Lysosomal Autophagy Inhibition.
Article in Cancer discovery, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 33 citations in OpenAlex.
- Biomimetic stress granules replenish lysosomal repair to reinstate macrophage immunometabolic antibacterial programs.Bioactive materials · 2027Article
- Nanomaterial-driven spatiotemporal autophagy modulation: The dual-edged sword in precision cancer therapy.Acta pharmaceutica Sinica. B · 2026Review
- The Lysosome-Cathepsin Axis in Pancreatic Cancer: Mechanisms of Stromal Remodeling, Immune Evasion, and Therapy Resistance.Biomolecules · 2026Review
- Deciphering the role of glycolipids as emerging therapeutic targets in EMT-driven cancer progression.Discover oncology · 2026Review
- Modeling lipid homeostasis using stable isotope tracing and flux analysis.Cell metabolism · 2026Article
- Magnolin overcomes EGFR TKI resistance in NSCLC by modulation of NDRG1-NRG2-HECW1 pathway.Acta pharmacologica Sinica · 2026Article
- Biomineralized OMV-based nanocomposite orchestrates cascade-amplified antitumor immunity via eliciting dual pyroptosis and blocking autophagy.Journal of nanobiotechnology · 2026Article
- Article
- Bioinformatic validation and machine learning based exploration of B cells-related gene signatures in the context of strategies for precision therapy to acute myeloid leukemia.Genes & diseases · 2026Article
- Modulation of the PGRMC1/NLRP7/HLA-C axis by autophagy is linked to both spontaneous preterm birth and gestational choriocarcinoma.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Tumorous cholesterol biosynthesis curtails anti-tumor immunity by preventing MTOR-TFEB-mediated lysosomal degradation of CD274/PD-L1.Autophagy · 2025Article
- Central Roles of Glucosylceramide in Driving Cancer Pathogenesis.International journal of molecular sciences · 2025Review
- Pancreatic Neuroendocrine Tumors Secrete Apolipoprotein E to Induce Tip Endothelial Cells That Remodel the Tumor-Stroma Ratio and Promote Cancer Progression.Cancer research · 2025Article
- Research progress on cholesterol metabolism and tumor therapy.Discover oncology · 2025Review
- Glycosphingolipids as emerging attack points in bladder cancer.Discover oncology · 2025Review
- Article
- Identification of key lipid metabolism-related genes in kidney fibrosis: implications for chronic kidney disease management.Frontiers in physiology · 2025Article
- UDP-Glucose Ceramide Glucosyltransferase Inhibition, Immune Cell Mediation, and Endometriosis Risk: A Mendelian Randomization Study.International journal of women's health · 2025Article
- The Drug Transporter P-Glycoprotein and Its Impact on Ceramide Metabolism-An Unconventional Ally in Cancer Treatment.International journal of molecular sciences · 2024Review
- Review
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
Lysosomal autophagy inhibition (LAI) with hydroxychloroquine or DC661 can enhance cancer therapy, but tumor regrowth is common. To elucidate LAI resistance, proteomics and immunoblotting demonstrated that LAI induced lipid metabolism enzymes in multiple cancer cell lines. Lipidomics showed that LAI increased cholesterol, sphingolipids, and glycosphingolipids. These changes were associated with striking levels of GM1+ membrane microdomains (GMM) in plasma membranes and lysosomes. Inhibition of cholesterol/sphingolipid metabolism proteins enhanced LAI cytotoxicity. Targeting UDP-glucose ceramide glucosyltransferase (UGCG) synergistically augmented LAI cytotoxicity. Although UGCG inhibition decreased LAI-induced GMM and augmented cell death, UGCG overexpression led to LAI resistance. Melanoma patients with high UGCG expression had significantly shorter disease-specific survival. The FDA-approved UGCG inhibitor eliglustat combined with LAI significantly inhibited tumor growth and improved survival in syngeneic tumors and a therapy-resistant patient-derived xenograft. These findings nominate UGCG as a new cancer target, and clinical trials testing UGCG inhibition in combination with LAI are warranted. SIGNIFICANCE: We discovered UGCG-dependent lipid remodeling drives resistance to LAI. Targeting UGCG with a drug approved for a lysosomal storage disorder enhanced LAI antitumor activity without toxicity. LAI and UGCG inhibition could be tested clinically in multiple cancers. This article is highlighted in the In This Issue feature, p. 247.
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Registered trials
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.