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WWOX activation by toosendanin suppresses hepatocellular carcinoma metastasis through JAK2/Stat3 and Wnt/β-catenin signaling.

Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Loss of WW-domain containing oxidoreductase (WWOX) has been proven to be associated with malignant metastasis in patients with HCC. In this study, by using a non-biased CRISPR knockout genetic screen targeting 19,050 human genes, we found that toosendanin (TSN) is a novel druggable WWOX candidate agonist for metastatic HCC patients. We also found that TSN exhibited significant anti-proliferative and anti-metastatic effects on HCC cells in a WWOX-dependent manner. Overexpression and knockdown of WWOX in vitro and in vivo confirmed that the suppression of HCC by TSN involved WWOX. TSN regulated Stat3, DVL2, and GSK3β by transforming their interactions with WWOX as demonstrated by a Co-IP assay. TSN accelerated the degradation of β-catenin by promoting the function of APC, AXIN1, CK1, and GSK3β complex. Nuclear translocation of p-Stat3 Y705 and β-catenin was impeded by the TSN-induced blockade of JAK2/Stat3 and Wnt/β-catenin signaling, accompanied by the inhibition of MMPs and C-MYC.
AuthorsTianfeng Yang, Rui Xu, Jian Huo, Bo Wang, Xia Du, Bingling Dai, Man Zhu, Yingzhuan Zhan, Dongdong Zhang, Yanmin Zhang
JournalCancer letters (Cancer Lett) Vol. 513 Pg. 50-62 (08 10 2021) ISSN: 1872-7980 [Electronic] Ireland
PMID34015398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 Elsevier B.V. All rights reserved.
Chemical References
  • Drugs, Chinese Herbal
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tumor Suppressor Proteins
  • toosendanin
  • WW Domain-Containing Oxidoreductase
  • WWOX protein, human
  • JAK2 protein, human
  • Janus Kinase 2
Topics
  • Carcinoma, Hepatocellular (drug therapy, pathology)
  • Drugs, Chinese Herbal (pharmacology, therapeutic use)
  • Humans
  • Janus Kinase 2 (metabolism)
  • Liver Neoplasms (drug therapy, pathology)
  • Neoplasm Metastasis
  • STAT3 Transcription Factor (metabolism)
  • Signal Transduction
  • Tumor Suppressor Proteins (metabolism)
  • WW Domain-Containing Oxidoreductase (metabolism)
  • Wnt Signaling Pathway

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