ADA-07 suppresses solar ultraviolet–induced skin carcinogenesis by directly inhibiting TOPK

Ge Gao, Tianshun Zhang, Qiushi Wang, Kanamata Reddy, Hanyong Chen, Ke Yao, Keke Wang, Eunmiri Roh, Tatyana Zykova, Weiya Ma, Joohyun Ryu, Clara N Curiel, David S Alberts, Sally E Dickinson, Ann M. Bode, Ying Xing, Zigang Dong

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1843-1854
Number of pages12
JournalMolecular Cancer Therapeutics
Volume16
Issue number9
DOIs
StatePublished - Sep 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Gao, G., Zhang, T., Wang, Q., Reddy, K., Chen, H., Yao, K., Wang, K., Roh, E., Zykova, T., Ma, W., Ryu, J., Curiel, C. N., Alberts, D. S., Dickinson, S. E., Bode, A. M., Xing, Y., & Dong, Z. (2017). ADA-07 suppresses solar ultraviolet–induced skin carcinogenesis by directly inhibiting TOPK. Molecular Cancer Therapeutics, 16(9), 1843-1854. https://doi.org/10.1158/1535-7163.MCT-17-0212