Cell growth inhibition by 3-deoxysappanchalcone is mediated by directly targeting the TOPK signaling pathway in colon cancer

Ran Zhao, Hai Huang, Bu Young Choi, Xuejiao Liu, Man Zhang, Silei Zhou, Mengqiu Song, Fanxiang Yin, Hanyong Chen, Jung Hyun Shim, Ann M. Bode, Zigang Dong, Mee Hyun Lee

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: Colorectal cancer is one of the most common causes of cancer death worldwide. Unfortunately, chemotherapies are limited due to many complications and development of resistance and recurrence. The T-lymphokine-activated killer cell-originated protein kinase (TOPK)is highly expressed and activated in colon cancer, and plays an important role in inflammation, proliferation, and survival of cancer cells. Therefore, suppressing TOPK activity and its downstream signaling cascades is considered to be a rational therapeutic/preventive strategy against colon cancers. Purpose: 3-Deoxysappanchalcone (3-DSC), a component of Caesalpinia sappan L., is a natural oriental medicine. In this study, we investigated the effects of 3-DSC on colon cancer cell growth and elucidated its underlying molecular mechanism of targeting TOPK. Study design and methods: To evaluate the effects of 3-DSC against colon cancer, we performed cell proliferation assays, propidium iodide- and annexin V-staining analyses and Western blotting. Targeting TOPK by 3-DSC was identified by a kinase-binding assay and computational docking models. Results: 3-DSC inhibited the kinase activity of TOPK, but not mitogen-activated protein kinase (MEK). The direct binding of 3-DSC with TOPK was explored using a computational docking model and binding assay in vitro and ex vivo. 3-DSC inhibited colon cancer cell proliferation and anchorage-independent cell growth, and induced G2/M cell cycle arrest and apoptosis. Treatment of colon cancer cells with 3-DSC induced expression of protein that are involved in cell cycle (cyclin B1)and apoptosis (cleaved-PARP, cleaved-caspase-3, and cleaved-caspase-7), and suppressed protein expressions of extracellular signal-regulated kinase (ERK)-1/2, ribosomal S6 kinase (RSK), and c-Jun, which are regulated by the upstream kinase, TOPK. Conclusion: 3-DSC suppresses colon cancer cell growth by directly targeting the TOPK- mediated signaling pathway.

Original languageEnglish (US)
Article number152813
JournalPhytomedicine
Volume61
DOIs
StatePublished - Aug 2019

Bibliographical note

Funding Information:
This work was supported by grant funding from National Institutes of Health , USA CA187027 , CA166011 , CA196639 and Key Program of Henan Province , China, Grant no. 161100510300 (Z.G.D), the National Natural Science Foundation of China NSFC81672767 (M.H.L), and the Henan Provincial Government, China.

Keywords

  • 3-Deoxysappanchalcone
  • Apoptosis
  • Colon cancer
  • G2/M cell cycle
  • TOPK

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