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ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2017-09-01 00:00:00 , DOI: 10.1158/1535-7163.mct-17-0212
Ge Gao 1, 2 , Tianshun Zhang 1 , Qiushi Wang 1 , Kanamata Reddy 1 , Hanyong Chen 1 , Ke Yao 1 , Keke Wang 1, 3 , Eunmiri Roh 1 , Tatyana Zykova 1 , Weiya Ma 1 , Joohyun Ryu 1 , Clara Curiel-Lewandrowski 4 , David Alberts 4 , Sally E. Dickinson 4 , Ann M. Bode 1 , Ying Xing 2 , Zigang Dong 1, 3
Affiliation  

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 in vitro 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. Mol Cancer Ther; 16(9); 1843–54. ©2017 AACR .

中文翻译:

ADA-07通过直接抑制TOPK抑制太阳紫外线诱导的皮肤致癌作用

累积暴露于太阳紫外线(SUV)辐射被认为是皮肤癌发展的主要病因。MAPK级联的激活迅速发生,并且在SUV诱导的细胞反应的调节中起着至关重要的作用。T-LAK细胞起源的蛋白激酶(TOPK)是MAPK的上游激活剂,与炎症,DNA损伤和肿瘤发展密切相关。但是,尚未阐明特定TOPK抑制剂在SUV诱导的皮肤癌中的化学预防和治疗作用。在当前的研究中,合成并表征了新型的TOPK抑制剂ADA-07。下拉测定结果,ATP竞争和体外激酶测定数据表明,ADA-07与TOPK在ATP结合口袋处相互作用,并抑制了其激酶活性。蛋白质印迹分析表明,ADA-07抑制SUV诱导的ERK1 / 2,p38和JNKs磷酸化,并随后抑制AP-1活性。重要的是,在暴露于慢性SUV的SKH-1无毛小鼠中,用ADA-07进行局部治疗可显着降低其肿瘤发生率,多样性和体积。我们的发现表明,ADA-07是针对SUV诱导的皮肤癌变的有前途的化学预防剂或潜在治疗剂,其通过特异性靶向TOPK发挥作用。分子癌疗法;16(9); 1843–54。©2017 AACR。我们的发现表明,ADA-07是针对SUV诱导的皮肤癌变的有前途的化学预防剂或潜在治疗剂,其通过特异性靶向TOPK发挥作用。分子癌疗法;16(9); 1843–54。©2017 AACR。我们的发现表明,ADA-07是针对SUV诱导的皮肤癌变的有前途的化学预防剂或潜在治疗剂,其通过特异性靶向TOPK发挥作用。分子癌疗法;16(9); 1843–54。©2017 AACR。
更新日期:2017-09-05
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