15-Deoxy-Δ^12,14-prostaglandin J₂ induces p53 expression through Nrf2-mediated upregulation of heme oxygenase-1 in human breast cancer cells

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-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) in human breast cancer (MCF-7) cells. Treatment of MCF-7 cells with 15d-PGJ₂ 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-PGJ₂ 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-PGJ₂–induced p53 expression. Upregulation of p53 expression by 15d-PGJ₂ 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-PGJ₂–induced p53 expression was attenuated. In addition, levels of the Fe-sequestering protein H-ferritin were elevated in 15d-PGJ₂-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.

Keywords::

• 15-Deoxy-Δ^12,14-prostaglandin J₂
• Heme oxygenase-1
• p53
• H-ferritin
• Cyclopentenone prostaglandin

Acknowledgments

The authors acknowledge the technical support and the fruitful discussion provided by Drs. Jozef Dulak and Alicza Jozkowicz of Jagiellonian University.

Funding

This work was supported by the Global Core Research Center (GCRC) grant (No. 2012-0001184) from the National Research Foundation (NRF), Republic of Korea.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.