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Mol Cancer Ther. 2019 Jul;18(7):1265-1277. doi: 10.1158/1535-7163.MCT-18-1241. Epub 2019 May 15.

17-Hydroxy Wortmannin Restores TRAIL's Response by Ameliorating Increased Beclin 1 Level and Autophagy Function in TRAIL-Resistant Colon Cancer Cells.

Author information

1
Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. wzheng@mail.nih.gov ykzhb@zju.edu.cn daimd@zju.edu.cn.
2
National Center for Advancing Translational Sciences (NCATS), NIH, Bethesda, Maryland.
3
Department of Biochemistry and Molecular Medicine, the George Washington University Medical School, Washington, D.C.
4
Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
5
Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
6
Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
National Center for Advancing Translational Sciences (NCATS), NIH, Bethesda, Maryland. wzheng@mail.nih.gov ykzhb@zju.edu.cn daimd@zju.edu.cn.
#
Contributed equally

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.

PMID:
31092562
PMCID:
PMC6606373
[Available on 2020-07-01]
DOI:
10.1158/1535-7163.MCT-18-1241

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