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15-Deoxy-Delta(12,14)-prostaglandin J(2) induces p53 expression through Nrf2-mediated upregulation of heme oxygenase-1 in human breast cancer cells

Cited 13 time in Web of Science Cited 14 time in Scopus
Authors
Kim, D. H.; Song, N. Y.; Kim, E. H.; Na, H. K.; Joe, Y.; Chung, H. T.; Surh, Young-Joon
Issue Date
2014-09
Citation
Free Radical Research, Vol.48 No.9, pp.1018-1027
Keywords
15-Deoxy-Delta(12,14)-prostaglandin J(2)Heme oxygenase-1p53H-ferritinCyclopentenone prostaglandin
Abstract
Heme oxygenase-1 (HO-1) is a stress-responsive enzyme that has antioxidant and cytoprotective functions. However, HO-1 has oncogenic functions in cancerous or transformed cells. In the present work, we investigated the effects of HO-1 on the expression of p53 induced by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) in human breast cancer (MCF-7) cells. Treatment of MCF-7 cells with 15d-PGJ(2) led to time-dependent increases in the expression of p53 as well as HO-1. Upregulation of p53 expression by 15d-PGJ2 was abrogated by si-RNA knock-down of HO-1. In MCF-7 cells transfected with HO-1 si-RNA, 15d-PGJ(2) failed to induce expression of p53 as well as HO-1. In addition, HO-1 inducers enhanced the p53 expression. We speculated that iron, a by-product of HO-1-catalyzed reactions, could mediate 15d-PGJ(2)-induced p53 expression. Upregulation of p53 expression by 15d-PGJ(2) was abrogated by the iron chelator desferrioxamine in MCF-7 cells. Iron released from heme by HO-1 activity is mostly in the Fe2+ form. When MCF-7 cells were treated with the Fe2+-specific chelator phenanthroline, 15d-PGJ(2)-induced p53 expression was attenuated. In addition, levels of the Fe-sequestering protein H-ferritin were elevated in 15d-PGJ(2)-treated MCF-7 cells. In conclusion, upregulation of p53 and p21 via HO-1 induction and subsequent release of iron with accumulation of H-ferritin may confer resistance to oxidative damage in cancer cells frequently challenged by redox-cycling anticancer drugs.
ISSN
1071-5762
URI
https://hdl.handle.net/10371/172745
DOI
https://doi.org/10.3109/10715762.2014.897343
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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