Non-melanoma skin cancer (NMSC) is a major health problem in the United States, with over two million new cases diagnosed yearly. Among many genetic and environmental factors contributed to NMSC, ultraviolet B (UVB) radiation is the major carcinogen. As with all solid tumors, angiogenesis is a necessary prerequisite for the progression and metastasis of NMSC. Thrombospondin-1 (TSP1) is the first endogenous inhibitor of angiogenesis to be identified, and its expression is markedly downregulated in epidermis following UVB irradiation and throughout distinct steps of skin carcinogenesis. Apigenin (4’, 5, 7-trihydroxyflavone), a nonmutagenic plant flavonoid, inhibits UV-induced NMSC in mice. However, the molecular mechanisms of apigenin's chemopreventive function remain elusive. For the first time, we found that apigenin restores normal TSP1 levels in UVB-irradiated skin keratinocytes in vitro and in vivo. The regulation of TSP1 expression in UVB/apigenin-treated keratinocytes occurs post-transcriptionally and is mediated by RNA-binding protein Human antigen R (HuR). Importantly, HuR has recently been demonstrated to play an important role in translation of TSP1 mRNA, and we showed that apigenin promotes cytoplasmic localization of HuR, where polyribosomal translation of TSP1 occurs. In addition, knockdown of HuR by siRNA abrogates the ability of apigenin to maintain normal TSP1 levels in UVB-irradiated keratinocytes. Furthermore, apigenin inhibits microvascular density (MVD) in superficial dermis that occurs in response to UVB irradiation. Taken together, our results demonstrate that apigenin promotes TSP1 expression in UVB-irradiated epidermis via HuR leading to inhibition of angiogenesis. Identifying TSP1 as a key target of apigenin and demonstrating its important role in chemoprevention by apigenin will provide a compelling rationale to use apigenin for maintaining the expression of protective TSP1 in the skin as a novel strategy for NMSC prevention and treatment.

Citation Format: Xin Tong, Bryan B. Bridgeman, Salida Mirzoeva, Susan E. Crawford, Olga V. Volpert, Jill C. Pelling. Targeting TSP1 and inhibiting angiogenesis in UV-induced skin cancer by apigenin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5075. doi:10.1158/1538-7445.AM2013-5075

©2013 American Association for Cancer Research
2013