ArticleMolecular cancer therapeutics2019
17-Hydroxy Wortmannin Restores TRAIL's Response by Ameliorating Increased Beclin 1 Level and Autophagy Function in TRAIL-Resistant Colon Cancer Cells.
Article in Molecular cancer therapeutics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 8 citations in OpenAlex.
- Systematic identification of cancer pathways and potential drugs for intervention through multi-omics analysis.The pharmacogenomics journal · 2025Article
- Wortmannin Inhibits Cell Growth and Induces Apoptosis in Colorectal Cancer Cells by Suppressing the PI3K/AKT Pathway.Anti-cancer agents in medicinal chemistry · 2024Article
- Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy.Acta pharmaceutica Sinica. B · 2023Review
- Inhibiting Cytoprotective Autophagy in Cancer Therapy: An Update on Pharmacological Small-Molecule Compounds.Frontiers in pharmacology · 2022Review
- Autophagy is a double-edged sword in the therapy of colorectal cancer.Oncology letters · 2021Review
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
Targeting of extrinsic apoptosis pathway by TNF-related apoptosis-inducing ligand (TRAIL) is an attractive approach for cancer therapy. However, two TRAIL drug candidates failed in clinical trials due to lack of efficacy. We identified 17-hydroxy wortmannin (17-HW) in a drug repurposing screen that resensitized TRAIL's response in the resistant colon cancer cells. The deficiency of caspase-8 in drug-resistant cells along with defects in apoptotic cell death was corrected by 17-HW, an inhibitor of PIK3C3-beclin 1 (BECN1) complex and autophagy activity. Further study found that BECN1 significantly increased in the TRAIL-resistant cells, resulting in increased autophagosome formation and enhanced autophagy flux. The extracellular domain (ECD) of BECN1 directly bound to the caspase-8 catalytic subunit (p10), leading to sequestration of caspase-8 in the autophagosome and its subsequent degradation. Inhibition of BECN1 restored the caspase-8 level and TRAIL's apoptotic response in the resistant colon cancer cells. An analysis of 120 colon cancer patient tissues revealed a correlation of a subgroup of patients (30.8%, 37/120) who have high BECN1 level and low caspase-8 level with a poor survival rate. Our study demonstrates that the increased BECN1 accompanied by enhanced autophagy activity is responsible for the TRAIL resistance, and a combination of TRAIL with a PIK3C3-BECN1 inhibitor is a promising therapeutic approach for the treatment of colon cancer.
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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.