17-hydroxy wortmannin restores TraIl's response by ameliorating increased beclin 1 level and autophagy function in TRAIL-resistant colon cancer cells

Sheng Dai, Shu Yang, Xin Hu, Wei Sun, Gregory Tawa, Wenge Zhu, Aaron D. Schimmer, Chao He, Bingliang Fang, Hongbo Zhu, Wei Zheng

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1265-1277
Number of pages13
JournalMolecular cancer therapeutics
Volume18
Issue number7
DOIs
StatePublished - Jan 1 2019

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TNF-Related Apoptosis-Inducing Ligand
Autophagy
Colonic Neoplasms
Caspase 8
Autoimmune Lymphoproliferative Syndrome
Drug Repositioning
wortmannin
Beclin-1
Pharmaceutical Preparations
Catalytic Domain
Cell Death
Therapeutics
Survival Rate
Clinical Trials
Apoptosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

17-hydroxy wortmannin restores TraIl's response by ameliorating increased beclin 1 level and autophagy function in TRAIL-resistant colon cancer cells. / Dai, Sheng; Yang, Shu; Hu, Xin; Sun, Wei; Tawa, Gregory; Zhu, Wenge; Schimmer, Aaron D.; He, Chao; Fang, Bingliang; Zhu, Hongbo; Zheng, Wei.

In: Molecular cancer therapeutics, Vol. 18, No. 7, 01.01.2019, p. 1265-1277.

Research output: Contribution to journalArticle

Dai, Sheng ; Yang, Shu ; Hu, Xin ; Sun, Wei ; Tawa, Gregory ; Zhu, Wenge ; Schimmer, Aaron D. ; He, Chao ; Fang, Bingliang ; Zhu, Hongbo ; Zheng, Wei. / 17-hydroxy wortmannin restores TraIl's response by ameliorating increased beclin 1 level and autophagy function in TRAIL-resistant colon cancer cells. In: Molecular cancer therapeutics. 2019 ; Vol. 18, No. 7. pp. 1265-1277.
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