Liquidambaric acid inhibits Wnt/β-catenin signaling and colon cancer via targeting TNF receptor-associated factor 2

  • Cell Rep. 2022 Feb 1;38(5):110319. doi: 10.1016/j.celrep.2022.110319.
Rong Yan  1 ,  Hongyan Zhu  1 ,  Piao Huang  1 ,  Min Yang  1 ,  Mengzhen Shen  1 ,  Yuting Pan  1 ,  Chengqian Zhang  2 ,  Xianglian Zhou  1 ,  Huiliang Li  3 ,  Xisong Ke  4 ,  Weidong Zhang  5 ,  Piliang Hao  6 ,  Yi Qu  7
Affiliations
  • 1. Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, P.R. China; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, China.
  • 2. School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, P.R. China.
  • 3. School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, P.R. China.
  • 4. Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, P.R. China; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, China. Electronic address: [email protected].
  • 5. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, China; School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, P.R. China. Electronic address: [email protected].
  • 6. School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, P.R. China. Electronic address: [email protected].
  • 7. Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, P.R. China; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Shanghai 201203, China. Electronic address: [email protected].
PMID: 35108540 DOI: 10.1016/j.celrep.2022.110319
Abstract

Wnt/β-catenin signaling is a well-established driver of colon cancer; however, a targeted therapeutic agent has not reached clinics yet. In the present study, we report that the natural compound liquidambaric acid (LDA) inhibits oncogenic Wnt/β-catenin signaling in vitro and in vivo through its direct target tumor necrosis factor receptor-associated factor 2 (TRAF2). Mechanistically, TRAF2 positively regulates Wnt signaling by interacting with the N-terminal of β-catenin via its TRAF-C domain; this interaction is disrupted in presence of LDA. Particularly, a TRAF2/β-catenin/TCF4/TNIK complex is present in colon Cancer cells, where TRAF2 is indispensable for the complex formation, and TRAF2/β-catenin and β-catenin/TCF4 interactions are disrupted upon LDA treatment. Our findings not only highlight that TRAF2 is an oncogenic regulator of Wnt/β-catenin signaling and colon Cancer but also provide a lead compound targeting TRAF2 for Cancer therapy.

Keywords
TRAF2; TRAF2/β-catenin/TCF4/TNIK complex; Wnt/β-catenin signaling; colorectal cancer; liquidambaric acid.
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