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

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. therapy of TRAIL with a BECN1-PIK3C3 complex inhibitor has potential as a new therapeutic approach for the subgroup of patients with colon cancer with an increased BECN1 level plus a reduced full-length caspase-8 level.

Rigosertib is more potent than wortmannin and rapamycin against adult T‐cell leukemia‐lymphoma

“…Here, wortmannin increased the Bax/Bcl-2 ratio, causing sub-G1 cell cycle arrest and apoptosis in Inf-3T3 and MT-2 cells. It was reported in previous works that wortmannin has pro-apoptotic and anti-metastatic effects in different types of malignancies, including pancreatic, 38 colon, 39 and lung cancers. 40 It is well established, in the literature, that mTORC1 inhibition leads to upregulation of receptor tyrosine kinases, including PDGFRs and IRS-1, increased PI3Kdependent Akt phosphorylation, PI3K-Ras activation, and in turn, an increase in MAPK signaling.…”

“…Here, wortmannin increased the Bax/Bcl‐2 ratio, causing sub‐G1 cell cycle arrest and apoptosis in Inf‐3T3 and MT‐2 cells. It was reported in previous works that wortmannin has pro‐apoptotic and anti‐metastatic effects in different types of malignancies, including pancreatic, 38 colon, 39 and lung cancers 40 …”

Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy

“…Compared with etoposide/cisplatin-sensitive groups, Beclin-1 expression was up-regulated in etoposide/cisplatin-resistant small cell lung cancer H446 and Letp cells and patient tissues and Beclin-1 inhibition reversed the in vitro chemoresistance of etoposide/cisplatin-resistant H446 and Letp cells 263 . Moreover, Beclin-1 significantly increased and autophagosome formation was increased in the TRAIL (TNF-related apoptosis-inducing ligand)-resistant colon cancer DLD1 cells, and Beclin-1 knockdown restores the response to TRAIL in resistant DLD1 cells 264 . Beclin-1 knockdown increased imatinib sensitivity in gastrointestinal stromal tumors GIST-T1 and GIST-882 cells, and miR-30a could sensitize these cells to imatinib via down-regulating Beclin-1 and inhibiting autophagy 265 .…”

Inhibiting Cytoprotective Autophagy in Cancer Therapy: An Update on Pharmacological Small-Molecule Compounds

“…Wortmannin shows an anti-tumor activity both alone and in combination with anti-cancer drugs like cisplatin to sensitizing radiation treatment ( Ihle et al, 2004 ). In addition, the analogue 17-hydroxy Wortmannin decreases drug resistance by restoring TRAIL’s response through ameliorating PIK3C3-beclin 1 (BECN1) complex and autophagy activity in colon cancer cells ( Dai et al, 2019 ). However, 3-MA exerts a dual role in the modulation of autophagy via different temporal patterns of inhibition on class I and III PI3K ( Wu et al, 2010 ).…”