Title: Blocking tumor cell eicosanoid synthesis by GP x 4 impedes tumor growth and malignancy
Authors: Heirman, Ingeborg ×
Ginneberge, Daisy
Brigelius-Flohé, Regina
Hendrickx, Nico
Agostinis, Patrizia
Brouckaert, Peter
Rottiers, Pieter
Grooten, Johan #
Issue Date: Jan-2006
Publisher: Pergamon
Series Title: Free Radical Biology & Medicine vol:40 issue:2 pages:285-94
Abstract: 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.
ISSN: 0891-5849
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Biochemistry Section (Medicine) (-)
Laboratory of Cell Death Research & Therapy
× corresponding author
# (joint) last author

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