Cyclooxygenase-2 uses the protein kinase C/ interleukin-8/urokinase-type plasminogen activator pathway to increase the invasiveness of breast cancer cells

Abstract

Abstract. Cyclooxygenase-2 (COX-2) increases breast cancer cell invasion. Expression of various pro-angiogenic and pro-invasive factors has been correlated with high expression of COX-2. However, whether these factors are essential to COX-2-mediated breast cancer invasion, and the mechanisms by which COX-2 increases the expression of these factors are unknown. Our microarray results indicate that higher COX-2 expression was associated with increased levels of interleukin-8 (IL-8), a key factor in breast cancer invasion and metastasis. COX-2 overexpressing cells (MCF-7/COX-2), generated by transfecting COX-2-encoding plasmids into the poorly invasive MCF-7 breast cancer cells, were more invasive and produced higher IL-8 levels than the parental cells. To investigate the role of IL-8 in COX-2-mediated invasion, MCF-7 parental cells were incubated with IL-8. Exogenous IL-8 increased the invasiveness of MCF-7 cells. IL-8 is one pathway by which COX-2 mediates breast cancer invasion.Protein kinase A (PKA) and protein kinase C (PKC) are activated by COX-2 and are involved in IL-8 regulation. Inhibition of PKC, not PKA, decreased IL-8 production and invasion in MCF-7/COX-2 cells. Activation of PKC, not PKA, increased IL-8 production and invasion in MCF-7 cells. Thus, the invasive effects of COX-2 are mediated by PKC, not PKA. Activity of the urokinase-type plasminogen activator (uPA) was increased in MCF-7 cells by COX-2 overexpression or by the addition of a PKC activator or by IL-8. Inhibition of PKC decreased uPA activity in MCF-7/COX-2 cells. Furthermore, inhibition of uPA activity decreased the invasiveness of MCF-7/COX-2 cells, indicating that uPA was essential to COX-2-mediated invasion. Herein we demonstrate for the first time a detailed mechanism by which COX-2 increases breast cancer invasion: the PKC/IL-8/uPA pathway.

Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

“…The invasiveness of the cells was assessed by Matrigel invasion assays as previously described [6]. Briefly, MCF-7, MCF-7/Vector and MCF-7PDCD4 cells (4 × 10 5 ) were cultured and treated with 10 μM PGE 2 or 100 ng/ml IL-8 for 24 h prior to the invasion assay.…”

“…High COX-2 expression in breast tumors has been correlated with poor survival, distant metastasis and lower local-regional control of disease [2,3]. Ectopic expression of COX-2 in breast cancer cell lines was found to increase the production of prostaglandin E 2 (PGE 2 ) and interleukin-8 (IL-8), which are essential to COX-2-induced breast cancer invasion [5][6][7]. However, which downstream factors are inhibited by the COX-2/ PGE 2 /IL-8-mediated pathway to induce breast cancer cell invasion are not known.…”

Anesthetic drug propofol inhibits the expression of interleukin‑6, interleukin‑8 and cyclooxygenase‑2, a potential mechanism for propofol in suppressing tumor development and metastasis

“…Singh et al (34) demonstrated the close interaction between IL-8 and COX-2 in bone metastasis of breast cancer. The correlation between the expression of IL-8 and COX-2 in breast cancer has also been highlighted by numerous studies (34,35), and it has been suggested that IL-8 and COX-2 are mutually regulated to promote the genesis and development of tumor (36). Therefore, the present study hypothesized that propofol may inhibit COX-2.…”

Interleukin-8 expression associated with canine mammary tumors

“…Simeone et al (2007) reported that high IL-8 expression promotes breast cancer metastasis. In addition to its relationship with angiogenesis, IL-8 is also associated with the metastatic phenotype and it promotes breast tumor cell potential, especially because this area receives a rich blood supply (De Larco et al, 2003;BobrovnikovaMarjon et al, 2004).…”

“…It acts along with vascular endothelial growth factor (VEGF) and eukaryotic initiation factor (eIF4E) (Zhou et al, 2006). In addition, cyclooxygenase-2 (COX-2) increases the invasiveness of breast cancer through IL-8 activation (Simeone et al, 2007).…”