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Cell growth inhibition by 3-deoxysappanchalcone is mediated by directly targeting the TOPK signaling pathway in colon
Ran Zhao1, Hai Huang2, Bu Young Choi3
1Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China; China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan, 450008, China.
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.
Insights
3-Deoxysappanchalcone (3-DSC) effectively inhibits colon cancer growth by targeting T-lymphokine-activated killer cell-originated protein kinase (TOPK). This natural compound suppresses proliferation and induces apoptosis, offering a potential therapeutic strategy against this deadly disease.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Colorectal cancer is a leading cause of cancer mortality globally.
- Current chemotherapies face limitations due to resistance, recurrence, and side effects.
- T-lymphokine-activated killer cell-originated protein kinase (TOPK) is crucial for colon cancer cell inflammation, proliferation, and survival.
Purpose of the Study:
- To investigate the anti-cancer effects of 3-Deoxysappanchalcone (3-DSC), a natural compound from Caesalpinia sappan L.
- To elucidate the molecular mechanisms by which 3-DSC targets and inhibits TOPK in colon cancer cells.
Main Methods:
- Cell proliferation assays, propidium iodide, and annexin V staining were used to evaluate 3-DSC's effects.
- Western blotting analyzed protein expression related to cell cycle and apoptosis.
- Kinase-binding assays and computational docking models identified 3-DSC's direct interaction with TOPK.
Main Results:
- 3-DSC directly inhibited TOPK kinase activity, but not MEK.
- The compound suppressed colon cancer cell proliferation, anchorage-independent growth, induced G2/M cell cycle arrest, and promoted apoptosis.
- 3-DSC modulated key proteins involved in cell cycle regulation (e.g., cyclin B1) and apoptosis (e.g., cleaved-PARP, cleaved-caspase-3/7), while downregulating TOPK- downstream targets like ERK1/2, RSK, and c-Jun.
Conclusions:
- 3-Deoxysappanchalcone (3-DSC) demonstrates significant anti-cancer activity against colon cancer.
- 3-DSC exerts its effects by directly targeting and inhibiting the TOPK-mediated signaling pathway.
- This study highlights 3-DSC as a promising agent for colon cancer therapy.
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