Blocking tumor cell eicosanoid synthesis by GP x 4 impedes tumor growth and malignancy.
Using tumor cell-restricted overexpression of glutathione peroxidase 4 (GP x 4), we investigated the contribution of tumor cell eicosanoids to solid tumor growth and malignant progression in two tumor models differing in tumorigenic potential. By lowering cellular lipid hydroperoxide levels, GP x 4 inhibits cyclooxygenase (COX) and lipoxygenase (LOX) activities. GP x 4 overexpression drastically impeded solid tumor growth of weakly tumorigenic L929 fibrosarcoma cells, whereas B16BL6 melanoma solid tumor growth was unaffected. Yet, GP x 4 overexpression did markedly increase the sensitivity of B16BL6 tumors to angio-destructive TNF-alpha therapy and abolished the metastatic lung colonizing capacity of B16BL6 cells. Furthermore, the GP x 4-mediated suppression of tumor cell prostaglandin E(2) (PGE(2)) production impeded the induction of COX-2 expression by the tumor stress conditions hypoxia and inflammation. Thus, our results reflect a PGE(2)-driven positive feedback loop for COX-2 expression in tumor cells. This was further supported by the restoration of COX-2 induction capacity of GP x 4-overexpressing L929 tumor cells when cultured in the presence of exogenous PGE(2). Thus, although COX-2 expression and eicosanoid production may be enabled by PGE(2) from the tumor microenvironment, our results demonstrate the predominant tumor cell origin of protumoral eicosanoids, promoting solid tumor growth of weakly tumorigenic tumors and malignant progression of strongly tumorigenic tumors.
Heirman
Ingeborg
I
Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Molecular Immunology Unit, Technologiepark 927, B-9052 Ghent, Belgium.
Ginneberge
Daisy
D
Brigelius-Flohé
Regina
R
Hendrickx
Nico
N
Agostinis
Patrizia
P
Brouckaert
Peter
P
Rottiers
Pieter
P
Grooten
Johan
J
D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018014:Gene Transfer Techniques; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008084:Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000235:genetics / Q000517:prevention & control*; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D013552:Swine; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000627:therapeutic use
D015777:Eicosanoids; D014409:Tumor Necrosis Factor-alpha; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D008084:Lipoxygenase; D051546:Cyclooxygenase 2; D015232:Dinoprostone