The Hormel Institute, University of Minnesota, Austin, Minnesota.
School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, P.R. China.
Mol Cancer Ther. 2017 Sep;16(9):1843-1854. doi: 10.1158/1535-7163.MCT-17-0212. Epub 2017 Jun 27.
Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the MAPK cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell-originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and characterized. Pull-down assay results, ATP competition, and kinase assay data revealed that ADA-07 interacted with TOPK at the ATP-binding pocket and inhibited its kinase activity. Western blot analysis showed that ADA-07 suppressed SUV-induced phosphorylation of ERK1/2, p38, and JNKs and subsequently inhibited AP-1 activity. Importantly, topical treatment with ADA-07 dramatically attenuated tumor incidence, multiplicity, and volume in SKH-1 hairless mice exposed to chronic SUV. Our findings suggest that ADA-07 is a promising chemopreventive or potential therapeutic agent against SUV-induced skin carcinogenesis that acts by specifically targeting TOPK. .
紫外线（UV）辐射的累积暴露被认为是皮肤癌发展的主要病因。MAPK 级联的激活迅速发生，对于调节 SUV 诱导的细胞反应至关重要。T-LAK 细胞起源的蛋白激酶（TOPK）是 MAPKs 的上游激活剂，它在炎症、DNA 损伤和肿瘤发展中起着重要作用。然而，特异性 TOPK 抑制剂在 SUV 诱导的皮肤癌中的化学预防和治疗作用尚未阐明。在本研究中，合成并表征了一种新型 TOPK 抑制剂 ADA-07。下拉测定结果、ATP 竞争和激酶测定数据表明，ADA-07 与 TOPK 在 ATP 结合口袋相互作用并抑制其激酶活性。Western blot 分析表明，ADA-07 抑制了 SUV 诱导的 ERK1/2、p38 和 JNKs 的磷酸化，从而抑制了 AP-1 活性。重要的是，局部应用 ADA-07 可显著减轻慢性 SUV 暴露的 SKH-1 无毛小鼠的肿瘤发生率、多发性和体积。我们的研究结果表明，ADA-07 是一种有前途的化学预防或潜在的治疗剂，可特异性靶向 TOPK ，用于预防 SUV 诱导的皮肤癌发生。
