3-Deoxysappanchalcone Inhibits Skin Cancer Proliferation by Regulating T-Lymphokine-Activated Killer Cell-Originated Protein Kinase in vitro and in vivo

Abstract

BackgroundSkin 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.PurposeIn 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.MethodsIn 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.Results3-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.ConclusionsOur 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.

Licochalcone D Inhibits Skin Epidermal Cells Transformation through the Regulation of AKT Signaling Pathways

“…To evaluate JB6 cell transformation, we conducted a cellular anchorage-independent transformation assay according to previous study ( Fu et al ., 2021 ). BME supplemented with 10% FBS, 2 mM L-glutamine, and 25 μg/mL gentamicin (Lonza Group Ltd., Basel, Switzerland) was mixed with 0.6% agar containing DMSO, EGF (10 ng/mL) or TPA (10 ng/mL) and/or LicoD (2.5, 5, 10 μM) or MK2206 (1, 3, 10 μM).…”

3-Deoxysappanchalcone Inhibits Cell Growth of Gefitinib-Resistant Lung Cancer Cells by Simultaneous Targeting of EGFR and MET Kinases

“…3-Deoxysappanchalcone (3-DSC, Fig. 1A ) is a natural chalcone compound derived from Caesalpinia sappan L. (Leguminosae), which has anti-inflammation, anti-allergy, anti-virus, and anti-oxidative activities ( Fu et al ., 2021 ; Kwak et al ., 2021 ). Caesalpinia sapan has long been used as a herbal medicine to improve blood circulation and protect against inflammation.…”

“…Caesalpinia sapan has long been used as a herbal medicine to improve blood circulation and protect against inflammation. In particular, 3-DSC shows pharmaceutical effects such as chemotherapeutic and chemopreventive functions against UV-induced skin hyperplasia and skin cancer growth through the inhibition of T-Lymphokine-Activated Killer Cell-Originated Protein Kinase ( Fu et al ., 2021 ). 3-DSC has been found to have anti-inflammatory effects in macrophages by activating AKT and mTOR pathways through an increase in hemeoxygenase-1 (HO-1) ( Kim et al ., 2014 ).…”

Synergistic effects of CuO/TiO2‐chitosan‐farnesol nanocomposites: Synthesis, characterization, antimicrobial, and anticancer activities on melanoma cells SK‐MEL‐3

“…Skin cancer is a global socioeconomic burden in this modern and industrialized society. Skin cancer has a few subgroups and has been named basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or melanoma [1,2]. Various factors like environmental agents, pollutants, radiation, and radiation from sunlight in the form of ultraviolet rays (UV rays) were considered to be risk factors for inducing Skin cancer [3].…”