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 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.

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.

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.

皮肤癌是全世界最常见的癌症之一。最具侵袭性的晚期皮肤癌的 5 年生存率在 20% 到 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剂至关重要。T 淋巴因子激活的杀伤细胞来源的蛋白激酶 (TOPK) 属于丝氨酸-苏氨酸激酶类，属于丝裂原活化蛋白激酶激酶 (MAPKK) 家族，在皮肤癌中高度表达和激活。本研究调查了植物衍生的功能性 TOPK 抑制剂 3-脱氧沙潘查尔酮 (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，我们阐明了 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和机制。

在一个体外研究，蛋白质印迹和体外激酶测定分别用于确定 TOPK 的蛋白质表达及其活性。使用 3-DSC 和 TOPK（野生型和 T42A/N172 突变）进行下拉测定以确认 TOPK 和 3-DSC 的 T42A/N172 氨基酸位点之间的直接相互作用。利用细胞增殖和不依赖锚定的细胞生长测定来确定 3-DSC 对细胞生长的影响。在一个体内研究中，在用 3-DSC 处理的急性 SSL 诱导的炎症小鼠模型或 SK-MEL-2 细胞衍生的异种移植小鼠模型中测量了皮肤的厚度和肿瘤大小。对从 SK-MEL-2 细胞衍生的异种移植物中分离的肿瘤进行免疫组织化学分析，以确定是否可以概括在 3-DSC 治疗中观察到的基于细胞的结果体内.

3-DSC通过调控TOPK及其相关信号通路，以贴壁依赖性和非贴壁依赖性方式抑制皮肤癌细胞增殖体外. 我们还发现 3-DSC 的应用减少了急性 SSL 诱导的小鼠皮肤增生。此外，我们观察到 3-DSC 通过减弱 TOPK 及其下游效应物（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。

我们的研究结果表明，3-DSC 可能通过分别防止紫外线诱导的皮肤增生和通过减弱 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能力。