ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK.
ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK.
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DOI：
10.1158/1535-7163.mct-17-0212
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发表时间：
2017-09
影响因子：
5.7
通讯作者：
Dong Z
中科院分区：
文献类型：
--
作者：
Gao G;Zhang T;Wang Q;Reddy K;Chen H;Yao K;Wang K;Roh E;Zykova T;Ma W;Ryu J;Curiel-Lewandrowski C;Alberts D;Dickinson SE;Bode AM;Xing Y;Dong Z
累积暴露于太阳紫外线(SUV)被认为是皮肤癌发生的主要病因。丝裂原活化蛋白激酶(MAPK)的激活发生得很快，并且在SUV诱导的细胞反应的调节中至关重要。T-LAK细胞起源的蛋白激酶(TOPK)是MAPKs的上游激活物，与炎症、DNA损伤和肿瘤的发生密切相关。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。本研究合成了一种新型TOPK抑制剂ADA-07，并对其进行了表征。Pull-down实验、ATP竞争实验和体外激酶实验结果表明，ADA-07与TOPK在ATP结合口袋处相互作用，并抑制其激酶活性。Western印迹分析表明，ADA-07可抑制SUV诱导的ERK1/2、p38和JNKs的磷酸化，进而抑制AP-1的活性。重要的是，ADA-07的局部治疗显著降低了暴露于慢性SUV的SKH-1无毛小鼠的肿瘤发生率、多样性和体积。我们的研究结果表明，ADA-07是一种有前景的化学预防或潜在的治疗药物，可通过特异性靶向TOPK来抑制SUV诱导的皮肤癌的发生。
Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the mitogen-activated protein kinase (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.
影响因子：
1.1
作者：
Burns EM;Tober KL;Riggenbach JA;Kusewitt DF;Young GS;Oberyszyn TM
通讯作者：
Oberyszyn TM