Fu Xiaorong, Zhao Ran, Yoon Goo, Shim Jung-Hyun, Choi Bu Young, Yin Fanxiang, Xu Beibei, Laster Kyle Vaughn, Liu Kangdong, Dong Zigang, Lee Mee-Hyun
Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, China.
China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.
Front Cell Dev Biol. 2021 Mar 25;9:638174. doi: 10.3389/fcell.2021.638174. eCollection 2021.
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.
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.
In an study, western blotting and 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 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 .
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 . 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.
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.
皮肤癌是全球最常被诊断出的癌症之一。最具侵袭性的晚期皮肤癌的5年生存率在20%至30%之间。因此，发现和研究能够有效治疗皮肤癌的新型靶向治疗药物至关重要。T淋巴细胞激活的杀伤细胞源蛋白激酶（TOPK）属于丝裂原活化蛋白激酶激酶（MAPKK）家族的丝氨酸 - 苏氨酸激酶类别，在皮肤癌中高度表达并被激活。本研究调查了植物源功能性TOPK抑制剂3 - 脱氧紫铆查耳酮（3 - DSC）在抑制皮肤癌细胞生长中的作用。
在皮肤癌预防和治疗的背景下，我们阐明3 - DSC对不同类型皮肤癌和太阳模拟光（SSL）诱导的皮肤增生的作用及机制。
在一项研究中，分别利用蛋白质印迹法和激酶测定来确定TOPK的蛋白表达及其活性。用3 - DSC与TOPK（野生型和T42A/N172突变体）进行下拉实验，以确认TOPK的T42A/N172氨基酸位点与3 - DSC之间的直接相互作用。利用细胞增殖和非锚定依赖性细胞生长实验来确定3 - DSC对细胞生长的影响。在另一项研究中，在急性SSL诱导的炎症小鼠模型或用3 - DSC处理的SK - MEL - 2细胞衍生的异种移植小鼠模型中测量皮肤厚度和肿瘤大小。对从SK - MEL - 2细胞衍生的异种移植中分离出的肿瘤进行免疫组织化学分析，以确定在3 - DSC处理后观察到的基于细胞的结果是否可以重现。
3 - DSC能够通过调节TOPK及其相关信号通路，以锚定依赖性和非锚定依赖性方式抑制皮肤癌细胞的增殖。我们还发现应用3 - DSC可减少急性SSL诱导的小鼠皮肤增生。此外，我们观察到3 - DSC通过减弱TOPK及其下游效应分子（包括ERK、RSK和c - Jun）的磷酸化来降低SK - MEL - 2细胞衍生的异种移植肿瘤的生长。
我们的结果表明，3 - DSC可能分别通过预防紫外线诱导的皮肤增生和减弱TOPK信号传导来抑制肿瘤细胞生长，从而发挥化学预防和化学治疗的作用。
