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A novel antioxidant 3-O-Caffeoyl-1-methylquinic acid enhances ultraviolet A-mediated apoptosis in immortalized HaCaT keratinocytes via Sp1-dependent transcriptional activation of p21WAF1/Cip1

Oncogene volume 26, pages 3559–3571 (2007)Cite this article

Abstract

It has become clear that ultraviolet A (UVA) radiation from the solar spectrum is a major environmental challenge to the skin. This necessitates developing novel mechanism-based agents capable of ameliorating UVA-induced effects in the skin. We recently described a novel antioxidant, 3-O-Caffeoyl-1-methylquinic acid (MCGA3) from leaves of bamboo. Here, we investigated the photochemopreventive effects of MCGA3 against UVA-mediated apoptosis in immortalized HaCaT keratinocytes. Pretreatment of MCGA3 rendered cells more sensitive to subsequent UVA irradiation-induced apoptosis as well as completely reversed UVA-induced sustained phosphorylation of extracellular signal-regulated kinase 1/2 and protein kinase Cα, downregulation of p21, and reactive oxygen species generation. Interestingly, MCGA3 itself effectively induced p21 protein and mRNA levels. Silencing of p21 by RNA interference revealed a pivotal role of p21 in generating G1-S arrest and in enhancing UVA-mediated apoptosis. Transcriptional activation of p21 by MCGA3 was mediated through the proximal region of multiple Sp1 sites regardless of p53-binding site in p21 promoter, and this effect was augmented by desferroioxamine, an iron chelating agent. Additional studies suggested that iron chelation-driven hypoxia by MCGA3 may function in activation of p21. MCGA3 could be a useful agent to prevent photocarcinogenesis via apoptotic elimination of p53 mutant and DNA-repair defective cells caused by UVA radiation.

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Acknowledgements

This research used the facilities and support provided by US PHS Grants ROI CA 78809, ROI CA 101039 and p50 DK 065303. We thank Dr Kimitris Kardassis (University of Crete Medical School, Herakleion, Greece) for p21 promoter constructs.

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Authors and Affiliations

  1. Department of Dermatology, University of Wisconsin, Madison, WI, USA

    M-H Kweon, F Afaq, K M R Bhat, V Setaluri & H Mukhtar

  2. School of Life Science and Biotechnology, Korea University, Seoul, Korea

    M-H Kweon

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  1. M-H Kweon
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  2. F Afaq
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  4. V Setaluri
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Correspondence to H Mukhtar.

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Kweon, MH., Afaq, F., Bhat, K. et al. A novel antioxidant 3-O-Caffeoyl-1-methylquinic acid enhances ultraviolet A-mediated apoptosis in immortalized HaCaT keratinocytes via Sp1-dependent transcriptional activation of p21WAF1/Cip1. Oncogene 26, 3559–3571 (2007). https://doi.org/10.1038/sj.onc.1210135

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