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.
Kim
Do-Hee
DH
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea.
Kim
Jung-Hyun
JH
Kim
Eun-Hee
EH
Na
Hye-Kyung
HK
Cha
Young-Nam
YN
Chung
Jin Ho
JH
Surh
Young-Joon
YJ
D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010618:Phenanthrolines / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011524:Protoporphyrins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014945:Wound Healing
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D007155:Immunologic Factors; D007502:Iron Chelating Agents; D061965:Matrix Metalloproteinase Inhibitors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010618:Phenanthrolines; D011524:Protoporphyrins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C017803:zinc protoporphyrin; D007501:Iron; D008156:Luciferases; D051547:Heme Oxygenase-1; D020781:Matrix Metalloproteinase 1; D015230:Prostaglandin D2; C025205:1,10-phenanthroline