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17-Hydroxy Wortmannin Restores TRAIL's Response by Ameliorating Increased Beclin 1 Level and Autophagy Function in
Sheng Dai1,2, Shu Yang2, Xin Hu2
1Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. wzheng@mail.nih.gov ykzhb@zju.edu.cn daimd@zju.edu.cn.
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.
Insights
17-hydroxy wortmannin (17-HW) restores TRAIL therapy efficacy in colon cancer by inhibiting beclin 1 (BECN1) and autophagy. This combination targets TRAIL-resistant cells with high BECN1 and low caspase-8, improving cancer treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Pathways
Background:
- Targeting the extrinsic apoptosis pathway with TNF-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy strategy.
- TRAIL-based drugs have faced challenges in clinical trials due to lack of efficacy in resistant cancers.
Purpose of the Study:
- To identify compounds that resensitize TRAIL-resistant colon cancer cells.
- To elucidate the mechanism of TRAIL resistance involving beclin 1 (BECN1) and autophagy.
Main Methods:
- Drug repurposing screen using 17-hydroxy wortmannin (17-HW).
- Investigation of caspase-8, beclin 1 (BECN1), and autophagy in TRAIL-resistant cells.
- Analysis of colon cancer patient tissues for BECN1 and caspase-8 levels and survival rates.
Main Results:
- 17-HW restored TRAIL sensitivity in resistant colon cancer cells by correcting caspase-8 deficiency and enhancing apoptosis.
- Increased BECN1 levels in resistant cells led to enhanced autophagy and sequestration/degradation of caspase-8.
- Inhibition of BECN1 restored caspase-8 levels and TRAIL-induced apoptosis.
- High BECN1 and low caspase-8 levels correlated with poor survival in a subgroup of colon cancer patients.
Conclusions:
- Elevated BECN1 and enhanced autophagy contribute to TRAIL resistance in colon cancer.
- Combining TRAIL with a PIK3C3-BECN1 inhibitor presents a potential therapeutic strategy for colon cancer treatment.