TY - JOUR
T1 - ADA-07 suppresses solar ultraviolet–induced skin carcinogenesis by directly inhibiting TOPK
AU - Gao, Ge
AU - Zhang, Tianshun
AU - Wang, Qiushi
AU - Reddy, Kanamata
AU - Chen, Hanyong
AU - Yao, Ke
AU - Wang, Keke
AU - Roh, Eunmiri
AU - Zykova, Tatyana
AU - Ma, Weiya
AU - Ryu, Joohyun
AU - Curiel-Lewandrowski, Clara
AU - Alberts, David
AU - Dickinson, Sally E.
AU - Bode, Ann M.
AU - Xing, Ying
AU - Dong, Zigang
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/9
Y1 - 2017/9
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-17-0212
DO - 10.1158/1535-7163.MCT-17-0212
M3 - Article
C2 - 28655782
AN - SCOPUS:85029456589
SN - 1535-7163
VL - 16
SP - 1843
EP - 1854
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 9
ER -