Critical role of endogenous heme oxygenase 1 as a tuner of the invasive potential of prostate cancer cells.
Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Inflammation has been recognized as a risk factor for this disease. Heme oxygenase 1 (HO-1), the inducible isoform of the rate-limiting enzyme in heme degradation, counteracts oxidative and inflammatory damage. Here, we investigated the regulated expression of HO-1 and its functional consequences in PCa. We studied the effect of genetic and pharmacologic disruption of HO-1 in the growth, invasion, and migration in androgen-sensitive (MDA PCa2b and LNCaP) and androgen-insensitive (PC3) PCa cell lines. Our results show that HO-1 levels are markedly decreased in PC3 compared with MDA PCa2b and LNCaP. Hemin treatment increased HO-1 at both protein and mRNA levels in all cell lines and decreased cell proliferation and invasion. Furthermore, overexpression of HO-1 in PC3 resulted in markedly reduced cell proliferation and migration. Accordingly, small interfering RNA-mediated silencing of HO-1 expression in MDA PCa2b cells resulted in increased proliferation and invasion. Using reverse transcription-quantitative PCR-generated gene array, a set of inflammatory and angiogenic genes were upregulated or downregulated in response to HO-1 overexpression identifying matrix metalloprotease 9 (MMP9) as a novel downstream target of HO-1. MMP9 production and activity was downregulated by HO-1 overexpression. Furthermore, PC3 cells stably transfected with HO-1 (PC3HO-1) and controls were injected into nu/nu mice for analysis of in vivo tumor xenograft phenotype. Tumor growth and MMP9 expression was significantly reduced in PC3HO-1 tumors compared with control xenografts. Taken together, these results implicate HO-1 in PCa cell migration and proliferation suggesting its potential role as a therapeutic target in clinical settings.
Gueron
Geraldine
G
Department of Biological Chemistry, School of Sciences, University of Buenos Aires, Buenos Aires, Argentina.
De Siervi
Adriana
A
Ferrando
Mercedes
M
Salierno
Marcelo
M
De Luca
Paola
P
Elguero
Belen
B
Meiss
Roberto
R
Navone
Nora
N
Vazquez
Elba S
ES
D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D014183:Transplantation, Heterologous
D034741:RNA, Small Interfering; D006427:Hemin; D051547:Heme Oxygenase-1; D020780:Matrix Metalloproteinase 9