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: Xin Tong, Salida Mirzoeva, Dorina Veliceasa, Bryan B Bridgeman, Philip Fitchev, Mona L Cornwell, Susan E Crawford, Jill C Pelling, Olga V Volpert
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 22 Pg. 11413-27 (Nov 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25526033 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• ELAV Proteins
• SPZ1 protein, human
• Thrombospondin 1
• Apigenin

Topics

• Animals
• Apigenin (pharmacology)
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Cell Growth Processes (drug effects, radiation effects)
• Chemoprevention (methods)
• ELAV Proteins (metabolism)
• Female
• Humans
• Keratinocytes (drug effects, metabolism, radiation effects)
• Mice
• Mice, Hairless
• Mice, Inbred BALB C
• Neoplasms, Radiation-Induced (blood supply, metabolism, prevention & control)
• Neovascularization, Pathologic
• Skin (blood supply, drug effects, metabolism, radiation effects)
• Skin Neoplasms (blood supply, metabolism, prevention & control)
• Thrombospondin 1 (metabolism)
• Ultraviolet Rays