A derivative of chrysin suppresses two-stage skin carcinogenesis by inhibiting mitogen- and stress-activated kinase 1

Haidan Liu, Joonsung Hwang, Wei Li, Tae Woong Choi, Kangdong Liu, Zunnan Huang, Jae Hyuk Jang, N. R. Thimmegowda, Ki Won Lee, In Ja Ryoo, Jong Seog Ahn, Ann M. Bode, Xinmin Zhou, Yifeng Yang, Raymond L. Erikson, Bo Yeon Kim, Zigang Dong

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Mitogen- and stress-activated kinase 1 (MSK1) is a nuclear serine/threonine protein kinase that acts downstream of both extracellular signal-regulated kinases and p38 mitogen-activated protein kinase in response to stress or mitogenic extracellular stimuli. Increasing evidence has shown that MSK1 is closely associated with malignant transformation and cancer development. MSK1 should be an effective target for cancer chemoprevention and chemotherapy. However, very few MSK1 inhibitors, especially natural compounds, have been reported. We used virtual screening of a natural products database and the active conformation of the C-terminal kinase domain of MSK1 (PDB id 3KN) as the receptor structure to identify chrysin and its derivative, compound 69407, as inhibitors of MSK1. Compared with chrysin, compound 69407 more strongly inhibited proliferation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ cells with lower cytotoxicity. Western blot data demonstrated that compound 69407 suppressed phosphorylation of the MSK1 downstream effector histone H3 in intact cells. Knocking down the expression of MSK1 effectively reduced the sensitivity of JB6 P+ cells to compound 69407. Moreover, topical treatment with compound 69407 before TPA application significantly reduced papilloma development in terms of number and size in a two-stage mouse skin carcinogenesis model. The reduction in papilloma development was accompanied by the inhibition of histone H3 phosphorylation at Ser10 in tumors extracted from mouse skin. The results indicated that compound 69407 exerts inhibitory effects on skin tumorigenesis by directly binding with MSK1 and attenuates the MSK1/histone H3 signaling pathway, which makes it an ideal chemopreventive agent against skin cancer.

Original languageEnglish (US)
Pages (from-to)74-85
Number of pages12
JournalCancer Prevention Research
Volume7
Issue number1
DOIs
StatePublished - Jan 2014

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