Suppression of the solar ultraviolet-induced skin carcinogenesis by TOPK inhibitor HI-TOPK-032.
Suppression of the solar ultraviolet-induced skin carcinogenesis by TOPK inhibitor HI-TOPK-032.
复制标题
DOI：
10.1038/s41388-020-1286-4
复制
发表时间：
2020-05
期刊：
影响因子：
8
通讯作者：
Dong Z
中科院分区：
文献类型：
--
作者：
Roh E;Han Y;Reddy K;Zykova TA;Lee MH;Yao K;Bai R;Curiel-Lewandrowski C;Dong Z
非黑色素瘤皮肤癌(NMSC)，如皮肤鳞状细胞癌(CSCC)，是由太阳紫外线(SUV)照射引起的，是美国最常见的癌症。T-LAK细胞起源的蛋白激酶(TOPK)是一种丝氨酸-苏氨酸激酶，在SUV照射下被激活，参与了皮肤癌变过程。将研究重点放在TOPK信号通路和皮肤癌发生的靶向治疗上的策略可能有助于发现针对皮肤癌的其他治疗方法。在本研究中，我们发现TOPK可以JNKs非依赖的方式直接结合和磷酸化作为AP-1核心成员之一的c-jun，作用于SSL63和Ser73。TOPK基因敲除或HI-TOPK-032(TOPK特异性抑制剂)可抑制皮肤癌细胞的集落形成和细胞增殖。与正常皮肤组织相比，人AK和CSCC中c-Jun的磷酸化水平显著升高，HI-TOPK-032对SCC细胞中c-Jun的磷酸化有抑制作用，且呈剂量依赖关系。此外，HI-TOPK-032可降低SSL诱导的AP-1反式激活活性。此外，局部应用HI-TOPK-032可减轻SKH1无毛小鼠由SSL引起的急性炎症。重要的是，HI-TOPK-032抑制了慢性SSL诱导的无毛小鼠皮肤癌变和c-jun磷酸化水平。结果表明，在皮肤癌变过程中，TOPK可磷酸化并激活c-jun的Ser63和Ser73位，HI-TOPK-032可作为一种潜在的化学预防药物用于预防CSCC的发生发展。
Nonmelanoma skin cancer (NMSC) such as cutaneous squamous cell carcinoma (cSCC) is caused by solar ultraviolet (SUV) exposure and is the most common cancer in the United States. T-LAK cell-originated protein kinase (TOPK), a serine-threonine kinase is activated by SUV irradiation and involved in skin carcinogenesis. Strategies with research focusing on the TOPK signaling pathway and targeted therapy in skin carcinogenesis may helpful for the discovery of additional treatments against skin cancer. In this study, we found that TOPK can directly bind to and phosphorylate c-Jun (as one of the core member of AP-1) at Ser63 and Ser73 after SSL exposure in a JNKs-independent manner. TOPK knocking down, or HI-TOPK-032 (TOPK specific inhibitor) attenuated colony formation and cell proliferation of skin cancer cells. Phosphorylated levels of c-Jun were overexpressed in human AK and cSCC compared with normal skin tissues, and HI-TOPK-032 inhibited the phosphorylation of c-Jun in SCC cell line in a dose-dependent manner. Furthermore, HI-TOPK-032 decreased SSL-induced AP-1 transactivation activity. Moreover, acute SSL-induced inflammation was attenuated by the topical application of HI-TOPK-032 in SKH1 hairless mice. Importantly, HI-TOPK-032 suppressed chronic SSL-induced skin carcinogenesis and c-Jun phosphorylation levels in SKH1 hairless mice. Our results demonstrate that TOPK can phosphorylate and activate c-Jun at Ser63 and Ser73 in the process of skin carcinogenesis and HI-TOPK-032 could be used as a potential chemopreventive drug against cSCC development.
登录
查看更多内容
影响因子：
4
作者：
Hess, J;Angel, P;Schorpp-Kistner, M
通讯作者：
Schorpp-Kistner, M
影响因子：
11.4
作者：
Behrens, A;Sibilia, M;Wagner, EF
通讯作者：
Wagner, EF
影响因子：
5.7
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
通讯作者：
Dong Z
DOI：
10.1002/hed.23100
发表时间：
2013-03
影响因子：
2.9
作者：
Loyo, Myriam;Li, Ryan J.;Bettegowda, Chetan;Pickering, Curtis R.;Frederick, Mitchell J.;Myers, Jeffrey N.;Agrawal, Nishant
通讯作者：
Agrawal, Nishant
影响因子：
11.2
作者：
Kim, Dong Joon;Li, Yan;Dong, Zigang
通讯作者：
Dong, Zigang