title: Chemopreventive apigenin controls UVB-induced cutaneous proliferation and angiogenesis through HuR and thrombospondin-1.
abstract: Plant flavonoid apigenin prevents and inhibits UVB-induced carcinogenesis in the skin and has strong anti-proliferative and anti-angiogenic properties. Here we identify mechanisms, by which apigenin controls these oncogenic events. We show that apigenin acts, at least in part, via endogenous angiogenesis inhibitor, thrombospondin-1 (TSP1). TSP1 expression by the epidermal keratinocytes is potently inhibited by UVB. It inhibits cutaneous angiogenesis and UVB-induced carcinogenesis. We show that apigenin restores TSP1 in epidermal keratinocytes subjected to UVB and normalizes proliferation and angiogenesis in UVB-exposed skin. Importantly, reconstituting TSP1 anti-angiogenic function in UVB-irradiated skin with a short bioactive peptide mimetic representing exclusively its anti-angiogenic domain reproduced the anti-proliferative and anti-angiogenic effects of apigenin. Cox-2 and HIF-1α are important mediators of angiogenesis. Both apigenin and TSP1 peptide mimetic attenuated their induction by UVB. Finally we identified the molecular mechanism, whereby apigenin did not affect TSP1 mRNA, but increased de novo protein synthesis. Knockdown studies implicated the RNA-binding protein HuR, which controls mRNA stability and translation. Apigenin increased HuR cytoplasmic localization and physical association with TSP1 mRNA causing de novo TSP1 synthesis. HuR cytoplasmic localization was, in turn, dependent on CHK2 kinase. Together, our data provide a new mechanism, by which apigenin controls UVB-induced carcinogenesis.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.affiliation: Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Salida
authors.initials: S
authors.lastname: Mirzoeva
authors.affiliation: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Dorina
authors.initials: D
authors.lastname: Veliceasa
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Bryan B
authors.initials: BB
authors.lastname: Bridgeman
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, St Louis, MO, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Fitchev
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, St Louis, MO, USA.
authors.forename: Mona L
authors.initials: ML
authors.lastname: Cornwell
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, St Louis, MO, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Pelling
authors.affiliation: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Volpert
mesh_terms: D000818:Animals; D047310:Apigenin / Q000494:pharmacology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D048708:Cell Growth Processes / Q000187:drug effects / Q000528:radiation effects; D018890:Chemoprevention / Q000379:methods; D051959:ELAV Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D008812:Mice, Hairless; D008807:Mice, Inbred BALB C; D009381:Neoplasms, Radiation-Induced / Q000098:blood supply / Q000378:metabolism / Q000517:prevention & control*; D009389:Neovascularization, Pathologic; D012867:Skin / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000517:prevention & control*; D019700:Thrombospondin 1 / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051959:ELAV Proteins; C481348:SPZ1 protein, human; D019700:Thrombospondin 1; D047310:Apigenin