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Published on: December 19, 2019
3-Deoxysappanchalcone Inhibits Skin Cancer Proliferation by Regulating T-Lymphokine-Activated Killer Cell-Originated
Xiaorong Fu1,2, Ran Zhao1,2, Goo Yoon3
1Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, China.
Background:
Skin cancer is one of the most commonly diagnosed cancers worldwide. The 5-year survival rate of the most aggressive late-stage skin cancer ranges between 20 and 30%. Thus, the discovery and investigation of novel target therapeutic agents that can effectively treat skin cancer is of the utmost importance. The T-lymphokine-activated killer cell-originated protein kinase (TOPK), which belongs to the serine-threonine kinase class of the mitogen-activated protein kinase kinase (MAPKK) family, is highly expressed and activated in skin cancer. The present study investigates the role of 3-deoxysappanchalcone (3-DSC), a plant-derived functional TOPK inhibitor, in suppressing skin cancer cell growth.
Purpose:
In the context of skin cancer prevention and therapy, we clarify the effect and mechanism of 3-DSC on different types of skin cancer and solar-simulated light (SSL)-induced skin hyperplasia.
Methods:
In an in vitro study, western blotting and in vitro kinase assays were utilized to determine the protein expression of TOPK and its activity, respectively. Pull-down assay with 3-DSC and TOPK (wild-type and T42A/N172 mutation) was performed to confirm the direct interaction between T42A/N172 amino acid sites of TOPK and 3-DSC. Cell proliferation and anchorage-independent cell growth assays were utilized to determine the effect of 3-DSC on cell growth. In an in vivo study, the thickness of skin and tumor size were measured in the acute SSL-induced inflammation mouse model or SK-MEL-2 cell-derived xenografts mouse model treated with 3-DSC. Immunohistochemistry analysis of tumors isolated from SK-MEL-2 cell-derived xenografts was performed to determine whether cell-based results observed upon 3-DSC treatment could be recapitulated in vivo.
Results:
3-DSC is able to inhibit cell proliferation in skin cancer cells in an anchorage-dependent and anchorage-independent manner by regulation of TOPK and its related signaling pathway in vitro. We also found that application of 3-DSC reduced acute SSL-induced murine skin hyperplasia. Additionally, we observed that 3-DSC decreased SK-MEL-2 cell-derived xenograft tumor growth through attenuating phosphorylation of TOPK and its downstream effectors including ERK, RSK, and c-Jun.
Conclusions:
Our results suggest that 3-DSC may function in a chemopreventive and chemotherapeutic capacity by protecting against UV-induced skin hyperplasia and inhibiting tumor cell growth by attenuating TOPK signaling, respectively.
Insights
3-deoxysappanchalcone (3-DSC) inhibits skin cancer growth by targeting T-lymphokine-activated killer cell-originated protein kinase (TOPK). This plant-derived compound shows potential for both preventing UV-induced skin hyperplasia and treating skin cancer.
Area of Science:
- Oncology
- Dermatology
- Pharmacology
Background:
- Skin cancer is a prevalent global malignancy with poor prognosis for advanced stages.
- T-lymphokine-activated killer cell-originated protein kinase (TOPK) is highly expressed and activated in skin cancer.
- Novel therapeutic agents targeting TOPK are crucial for effective skin cancer treatment.
Purpose of the Study:
- To investigate the anti-cancer effects and mechanisms of 3-deoxysappanchalcone (3-DSC) on various skin cancers.
- To evaluate 3-DSC's efficacy in preventing solar-simulated light (SSL)-induced skin hyperplasia.
Main Methods:
- In vitro studies utilized western blotting and kinase assays to assess TOPK activity and 3-DSC interaction.
- Cell proliferation and anchorage-independent growth assays determined 3-DSC's impact on cancer cell growth.
- In vivo studies involved SSL-induced skin hyperplasia and xenograft mouse models to measure 3-DSC's therapeutic effects.
Main Results:
- 3-DSC inhibited skin cancer cell proliferation in vitro by regulating TOPK signaling.
- Topical application of 3-DSC reduced acute SSL-induced skin hyperplasia in mice.
- 3-DSC decreased xenograft tumor growth by attenuating TOPK phosphorylation and downstream signaling.
Conclusions:
- 3-DSC demonstrates potential as a chemopreventive agent against UV-induced skin hyperplasia.
- 3-DSC exhibits chemotherapeutic properties by inhibiting skin tumor growth via TOPK pathway attenuation.
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