Screening for Chemical Suppressors of the Wnt/β-catenin Signaling Pathway

Abstract

Aberrant activation of Wnt/b-catenin canonical signaling is observed in multiple malignant tumors, and is recognized as an attractive therapeutic target for molecular targeted drugs. This signaling pathway is also involved in maintaining pluripotency in adult stem cells. Therefore, lowering potential stem cell toxicity is a key factor for the development of a Wnt/b-catenin signaling inhibitor. Here, we show Wnt/b-catenin pathway inhibitors with low toxicity, identied through phenotype-based screening using zebraˆsh embryos. Artiˆcial activation of the Wnt/b-catenin pathway in fertilized eggs, which are often considered the``ultimate stem cells'', results in an``eyeless'' phenotype in zebraˆsh embryos. Screening for compounds that rescue this``eyeless'' phenotype and have no eŠects on normal embryogenesis could help us identify Wnt/b-catenin pathway inhibitors with minimal stem cell toxicities, at least at a concentration that suppresses aberrant signaling. Chemical suppressors of the``eyeless'' phenotype include novel and known compounds with diŠerent modes of action. Some of these compounds diminish the activation of crosstalk between other signaling pathways and the Wnt/b-catenin pathway. These inhibitors reduced tumor growth in ApcMin/＋ mice and did not show apparent toxicities. Thus, our screening for chemical suppressors of the``eyeless'' phenotype allowed us to successfully identify inhibitors for the Wnt/b-catenin pathway with low toxicity.

A novel 7‑hypoxia‑related long non‑coding RNA signature associated with prognosis and proliferation in melanoma

“…The aberrant activation of canonical Wnt/β-catenin signalling is observed in multiple malignant tumours and is recognised as an attractive therapeutic target for molecular drugs ( 47 ). It has been reported that Wnt serves a crucial role in tumorigenesis and malignancy, which contributes to tumour proliferation and differentiation, survival, stress response and resistance ( 48 ).…”

Autophagy Machinery as a Promising Therapeutic Target in Endometrial Cancer

“…Hedgehog signaling pathway inhibitors have been shown to successfully impair proliferation of endometrial cancer cells (86), and mTOR inhibitors have also been investigated for their therapeutic potential in endometrial cancers (87). Itraconazole is a common antifungal agent that inhibited Hedgehog and AKT/mTOR signaling transducers as well as WNT/β-catenin signaling (88) and showed a dose- and time-dependent suppression of cell proliferation in human endometrial cancer cell lines (89). Tsubamoto and coworkers reported that this fungal agent also suppressed the proliferation of AN3-CA, HEC-1A, and Ishikawa cells, but did not suppress GLI1 or GLI2 transcription, downstream effectors of the Hedgehog pathway in HEC-50B or SNG-II cells (90).…”

The therapeutic effect of traditional Chinese medicine on breast cancer through modulation of the Wnt/β-catenin signaling pathway

“…Over the past decades, extensive research has illuminated the central role this pathway plays in breast cancer, influencing processes such as proliferation ( Wend et al, 2013 ), metastasis ( Luga et al, 2012 ; Harper et al, 2016 ), stem cell maintenance ( Wang et al, 2016 ), drug resistance ( Piva et al, 2014 ), and phenotyping ( Piva et al, 2014 ; Jiang et al, 2019 ). It has been found that the Wnt/β-catenin axis is the core component of the Wnt signaling pathway, making the design of targeted therapy for it a growing research focus ( Hernandez et al, 2012 ; Nishiya, 2017 ). However, despite the evident anti-cancer potential of inhibitors targeting this axis ( Kahn, 2014 ), their translation from research labs to clinical application has encountered numerous obstacles.…”