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Carcinogenesis Advance Access published online on January 9, 2009
Carcinogenesis, doi:10.1093/carcin/bgp012
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

15-Deoxy-{Delta}12,14-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

Do-Hee Kim1, Jung-Hyun Kim1,2, Eun-Hee Kim1, Hye-Kyung Na1, Young-Nam Cha3, Jin Ho Chung4 and Young-Joon Surh1,2

1 National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul 151-742
2 Cancer Research Institute, Seoul National University, Seoul 110-799
3 Department of Pharmacology and Toxicology, College of Medicine, Inha University, Incheon 382-751
4 Department of Dermatology, Seoul National University College of Medicine, Seoul 110-799, South Korea

Address for correspondence: Professor Young-Joon Surh, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea, Phone) +82 2 880-7845; Fax) +82 2 874-9775, E-mail) surh{at}plaza.snu.ac.kr.

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 µM of 15-deoxy-{Delta}12,14-prostaglandin J2 (15d-PGJ2) increased the expression and the activity of HO-1, which preceded the induction of matrix metalloproteinases (MMP-1). The 15d-PGJ2–induced up-regulation of MMP-1 was abrogated by the HO-1 inhibitor zinc protophorphyrin IX (ZnPP) as well as introduction of HO-1 siRNA. In addition, HO-1 inducers, such as cobalt protoporphyrin IX and hemin, up-regulated 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 phenanthroline. The iron chelators as well as the antioxidant NAC abrogated ROS formation by 15d-PGJ2. In conclusion, 15d-PGJ2 up-regulates 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.

Key Words: 15-deoxy-{Delta}12,14-prostaglandin J2 • cyclopentenone prostanglandin • heme oxygenase-1 • matrix metalloproteinase-1 • breast cancer metastasis

The first two authors equally contributed to this work.

Received August 15, 2008; revised December 16, 2008; accepted January 6, 2009.


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