Journal
CARCINOGENESIS
Volume 30, Issue 4, Pages 645-654Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgp012
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Funding
- Korea Science and Engineering Foundation through the National Research Laboratory Program [M10400000366-06J0000-36610]
- Ministry of Science and Technology, Republic of Korea [R11-2007-107-01002-0]
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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 mu M of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) increased the expression of HO-1, which preceded the induction of matrix metalloproteinases (MMPs). The 15d-PGJ(2)-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-PGJ(2)-treated MCF-7 cells. MCF-7 cells treated with 15d-PGJ(2) 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-PGJ(2), is transiently available for the stimulation of intracellular ROS generation and subsequently MMP-1 expression. 15d-PGJ(2)-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-PGJ(2). In conclusion, 15d-PGJ(2) 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.
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