Migratory activity of human breast cancer cells is modulated by differential expression of xanthine oxidoreductase

Abstract

Xanthine oxidoreductase (XOR) may exert an important, but poorly defined, role in the pathogenesis of breast cancer (BC). Loss of XOR expression was linked to aggressive BC, and recent clinical observations have suggested that decreasing XOR may be functionally linked to BC aggressiveness. The goal of the present investigation was to determine whether the decreased XOR observed in clinically aggressive BC was an intrinsic property of highly invasive mammary epithelial cells (MEC). Expression of XOR was investigated using HC11 mouse MEC, HB4a and MCF-10A normal human MEC, and several human mammary tumor cells including MCF-7 and MDA-MB-231. Consistent with clinical observations, data shown here revealed high levels of XOR in normal HC11 and MCF-10A cells that was markedly reduced in highly invasive mammary tumor cells. The contribution of XOR to tumor cell migration in vitro was investigated using MDA-MB-231 and MCF-7 cells and clonally selected derivatives of HC11 that exhibit either weak or strong migration in vitro. We observed that over-expression of an XOR cDNA in MDA-MB-231 and in HC11-C24, both possessing weak XOR expression and high migratory capacity, inhibited their migration in vitro. Conversely, pharmacological inhibition of XOR in MCF-7 and HC11-C4, both possessing high XOR expression and weak migratory capacity, stimulated their migration in vitro. Further experiments suggested that XOR derived ROS mediated this effect and also modulated COX-2 and MMP levels and function. These data demonstrate a functional link between XOR expression and MEC migration and suggest a potential role for XOR in suppressing BC pathogenesis.

Xanthine Oxidoreductase Promotes the Inflammatory State of Mononuclear Phagocytes through Effects on Chemokine Expression, Peroxisome Proliferator-activated Receptor-γ Sumoylation, and HIF-1α

“…First, to determine whether XOR overexpression would block IL-4 induced SUMO-PPAR␥, RAW264.7 cells were transfected with pCMV-Myc-XOR at various doses of input DNA. pCMV-Myc-XOR is a cDNA expression vector containing a functional XOR cDNA that is expressed under the control of the CMV constitutive promoter and produces ectopic overexpression of XOR (54). We observed that ectopic overexpression of XOR dose-dependently reduced levels of SUMO-PPAR␥ in IL-4-treated RAW264.7 cells (Fig.…”

Metabolomic network analysis of estrogen-stimulated MCF-7 cells: a comparison of overrepresentation analysis, quantitative enrichment analysis and pathway analysis versus metabolite network analysis

“…Estrogen has been reported to decrease both protein levels and enzyme activity of xanthine dehydrogenase/xanthine oxidase (XDH/XO) in MCF-7 cells (Taibi et al, 2008). Loss of XO activity has been linked to aggressive breast cancer growth both in vivo and in vitro (Fini et al, 2008). The phenotypic significance is unclear but offers an intriguing hypothesis that would require further exploration with an approach tailored to this goal.…”

Knockdown of OLA1, a regulator of oxidative stress response, inhibits motility and invasion of breast cancer cells

“…Apparently opposite effects of ROS have been observed. For example, in some cancer cells overproduction of endogenous ROS inhibits migratory activity, whereas depletion of ROS by introducing antioxidants or antioxidant enzymes to the cells stimulates migration (Fini et al, 2008;Shim et al, 2006). Clearly, additional studies are needed to resolve this contradiction and to further determine the mechanisms by which ROS affect cancer cell migration and invasion.…”