Silencing of Cyclooxygenase-2 Inhibits Metastasis and Delays Tumor Onset of Poorly Differentiated Metastatic Breast Cancer Cells

Abstract

Cyclooxygenases (COX) are rate-limiting enzymes involved in the conversion of PLA 2 -mobilized arachidonic acid into prostaglandins and thromboxanes. COX-2 is a key mediator of inflammation during both physiologic and pathologic responses to endogenous stimuli and infectious agents. Its overexpression has been detected in different cancers, including that of the breast. Using RNA interference, we have reduced the expression of COX-2 in the highly malignant breast cancer cell line MDA-MB-231 below detectable levels in response to interleukin-1B or 12-O-tetradecanoylphorbol-13-acetate treatment. Microarray analysis showed that COX-2 silencing resulted in the loss of mRNA expression of several oncogenic markers, such as matrix metalloproteinase-1, chemokine (C-X-C motif) receptor 4, and interleukin-11, which have been correlated with poor disease outcome, and in the up-regulation of antimetastatic transcripts, such as thrombospondin-1 and Epstein-Barr-Induced 3. Cells lacking COX-2 were less able to invade reconstituted extracellular matrix than parental cells in vitro. Consistent with these changes, loss of COX-2 resulted in the abolition or the significant delay of tumor onset when the cells were injected in the mammary fat pad of severe combined immunodeficient mice. Finally, silencing of COX-2 resulted in the inhibition of metastasis to the lungs of severe combined immunodeficient mice after intravenous injection. These data show that silencing of COX-2 abolishes the metastatic potential of MDA-MB-231 cells in vivo.

Cancer chemopreventive effects of starfish polysaccharide in human breast cancer cells

“…High PGE 2 levels are observed in many human breast cancers [5], and COX-2 is closely involved in tumor growth, invasion, and metastasis [14]. Consequently, COX-2 is considered a target for breast cancer therapy and chemoprevention strategies.…”

“…Masferrer et al (2000) and Kundu and Fulton (2002) demonstrated antiangiogenic, antimetastatic, and antitumor activities of COX-2 inhibitors [7,15]. Another study found that silencing COX-2 in MDA-MB-231 cells led to the induction of antiangiogenic gene expression and the reduction of prometastatic transcription [14]. In the present research, starfish polysaccharide effectively inhibited TPA-induced COX-2 expression in MDA-MB-231 breast cancer cells in a dose-dependent manner (Fig.…”

Cyclooxygenase-2 Enzyme Induces the Expression of the -2,3-Sialyltransferase-3 (ST3Gal-I) in Breast Cancer

“…Indeed, elevated levels of COX-2 in breast cancers are associated with a poor prognosis and ductal carcinoma in situ recurrence (18). Studies show that COX-2 is involved in breast cancer cell proliferation, migration, and invasion (19,21), and when the enzyme is knocked out, mice develop fewer mammary tumors (22), whereas overexpression of COX-2 in the mammary gland induces tumors (23). Moreover, although sometimes contradictory, epidemiological evidence suggests a correlation of intake of non-steroidal anti-inflammatory drugs (inhibitors of the COX enzymes) with decreased risk of breast cancer (24).…”

Potent Antitumor Activity in Experimental Hepatocellular Carcinoma by Adenovirus-Mediated Coexpression of TRAIL and shRNA against COX-2

“…In contrast to fetal hepatocytes, which expressed COX-2 in response to proinflammatory stimuli, adult hepatocytes failed to express COX-2 regardless of the type of challenge (19). However, overexpression of COX-2 was commonly related to different types of carcinomas, including hepatocellular carcinoma (20)(21)(22)(23). It was evident that COX-2 could enhance hepatocellular carcinoma invasiveness by promoting hepatocellular carcinoma proliferation and tumor angiogenesis (24,25).…”

“…Recent studies showed that downregulation of COX-2 expression via RNAi inhibited tumor cell proliferation and colony formation in vitro in different types of cancer cells (2,23,24). COX-2 silencing abolished the metastatic potential of the highly malignant breast cancer cells (21). Therefore, in this study we constructed an adenoviral vector with newly developed coexpression system to express shRNA against COX-2 and the therapeutic gene TRAIL and explored its antitumor potential in experimental hepatocellular carcinoma.…”