title: A derivative of chrysin suppresses two-stage skin carcinogenesis by inhibiting mitogen- and stress-activated kinase 1.
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.
authors.affiliation: University of Minnesota, 801 16th Avenue NE, Austin, MN 55912. Phone: 507-437-9600; Fax: 507-437-9606; zgdong@hi.umn.edu; and Bo-Yeon Kim, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon 363-883, Republic of Korea. bykim@kribb.re.kr.
authors.forename: Haidan
authors.initials: H
authors.lastname: Liu
authors.forename: Joonsung
authors.initials: J
authors.lastname: Hwang
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Tae Woong
authors.initials: TW
authors.lastname: Choi
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.forename: Zunnan
authors.initials: Z
authors.lastname: Huang
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Jang
authors.forename: N R
authors.initials: NR
authors.lastname: Thimmegowda
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: In-Ja
authors.initials: IJ
authors.lastname: Ryoo
authors.forename: Jong-Seog
authors.initials: JS
authors.lastname: Ahn
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Xinmin
authors.initials: X
authors.lastname: Zhou
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Yang
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Erikson
authors.forename: Bo-Yeon
authors.initials: BY
authors.lastname: Kim
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D047309:Flavones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D010212:Papilloma / Q000517:prevention & control; D010627:Phenethylamines / Q000494:pharmacology*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects; D012878:Skin Neoplasms / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C000591386:69407 compound; D016588:Anticarcinogenic Agents; D047309:Flavones; D005419:Flavonoids; D006657:Histones; D010627:Phenethylamines; C043561:chrysin; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate