title: Kaempferol targets RSK2 and MSK1 to suppress UV radiation-induced skin cancer.
abstract: Solar UV (SUV) irradiation is a major factor in skin carcinogenesis, the most common form of cancer in the United States. The MAPK cascades are activated by SUV irradiation. The 90 kDa ribosomal S6 kinase (RSK) and mitogen and stress-activated protein kinase (MSK) proteins constitute a family of protein kinases that mediate signal transduction downstream of the MAPK cascades. In this study, phosphorylation of RSK and MSK1 was upregulated in human squamous cell carcinoma (SCC) and SUV-treated mouse skin. Kaempferol, a natural flavonol, found in tea, broccoli, grapes, apples, and other plant sources, is known to have anticancer activity, but its mechanisms and direct target(s) in cancer chemoprevention are unclear. Kinase array results revealed that kaempferol inhibited RSK2 and MSK1. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that kaempferol interacts with RSK2 and MSK1 at the ATP-binding pocket and inhibits their respective kinase activities. Mechanistic investigations showed that kaempferol suppresses RSK2 and MSK1 kinase activities to attenuate SUV-induced phosphorylation of cAMP-responsive element binding protein (CREB) and histone H3 in mouse skin cells. Kaempferol was a potent inhibitor of SUV-induced mouse skin carcinogenesis. Further analysis showed that skin from the kaempferol-treated group exhibited a substantial reduction in SUV-induced phosphorylation of CREB, c-Fos, and histone H3. Overall, our results identify kaempferol as a safe and novel chemopreventive agent against SUV-induced skin carcinogenesis that acts by targeting RSK2 and MSK1.
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.|Pathophysiology Department, Basic Medical College, Zhengzhou University, No.100 Kexue Road, Henan, China, 450001.
authors.forename: Ke
authors.initials: K
authors.lastname: Yao
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.|Pathophysiology Department, Basic Medical College, Zhengzhou University, No.100 Kexue Road, Henan, China, 450001.
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Langfald
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.|Pathophysiology Department, Basic Medical College, Zhengzhou University, No.100 Kexue Road, Henan, China, 450001.
authors.forename: Ge
authors.initials: G
authors.lastname: Yang
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.|Pathophysiology Department, Basic Medical College, Zhengzhou University, No.100 Kexue Road, Henan, China, 450001.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Yu
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.
authors.forename: Myoung Ok
authors.initials: MO
authors.lastname: Kim
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.
authors.forename: Ki Beom
authors.initials: KB
authors.lastname: Bae
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.
authors.forename: Hong-Gyum
authors.initials: HG
authors.lastname: Kim
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.
authors.forename: Wei-Ya
authors.initials: WY
authors.lastname: Ma
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: Pathophysiology Department, Basic Medical College, Zhengzhou University, No.100 Kexue Road, Henan, China, 450001.
authors.forename: Ziming
authors.initials: Z
authors.lastname: Dong
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007150:Immunohistochemistry; D044949:Kaempferols / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation / Q000528:radiation effects; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013472:Sunlight / Q000009:adverse effects; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D044949:Kaempferols; C006552:kaempferol; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3