15-Deoxy-Delta12,14-prostaglandin J2 upregulates the expression of heme oxygenase-1 and subsequently matrix metalloproteinase-1 in human breast cancer cells: possible roles of iron and ROS.

Heme oxygenase-1 (HO-1) has recently been found to be involved in angiogenesis and metastasis. In this study, we investigated whether HO-1 could potentiate the metastatic potential of human breast cancer cells. Treatment of MCF-7 and MDA-MB-231 cells with 30 microM of 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) increased the expression of HO-1, which preceded the induction of matrix metalloproteinases (MMPs). The 15d-PGJ2-induced upregulation of MMP-1 was abrogated by the HO-1 inhibitor zinc protoporphyrin IX (ZnPP) as well as introduction of HO-1 short interfering RNA. In addition, HO-1 inducers, such as cobalt protoporphyrin IX and hemin, upregulated the expression of MMP-1. Overexpression of HO-1 in the MCF-7 cells caused the induction of MMP-1 expression. Treatment with the HO-1 inhibitor ZnPP abolished the migrative phenotype of 15d-PGJ2-treated MCF-7 cells. MCF-7 cells treated with 15d-PGJ2 exhibited intracellular accumulation of reactive oxygen species (ROS) which was abolished by ZnPP. We hypothesize that excess iron, released as a consequence HO-1 activity induced by 15d-PGJ2, is transiently available for the stimulation of intracellular ROS generation and subsequently MMP-1 expression. 15d-PGJ2-mediated upregulation of MMP-1 expression was blocked by the iron chelator desferrioxamine and the Fe2+-specific chelator 1,10-phenanthroline. The iron chelators as well as the antioxidant N-acetyl-L-cysteine abrogated ROS formation by 15d-PGJ2. In conclusion, 15d-PGJ2 upregulates MMP-1 expression via induction of HO-1 and subsequent production of iron capable of generating ROS, which may contribute to increased metastasis and invasiveness of the human breast cancer cells.