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Cyclooxygenase-2 Overexpression Inhibits Cathepsin D-Mediated Cleavage of Plasminogen to the Potent Antiangiogenic Factor Angiostatin

Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The University of Edinburgh Academic Centre, Chancellor’s Building, Edinburgh, Scotland EH16 4SB, United Kingdom

Address all correspondence and requests for reprints to: Dr. Henry N. Jabbour, Medical Research Council Human Reproductive Sciences Unit, The University of Edinburgh Academic Centre, Chancellor’s Building, 49 Little France Crescent, Edinburgh, Scotland EH16 4SB, United Kingdom. E-mail: h.jabbour{at}hrsu.mrc.ac.uk.

Overexpression of cyclooxygenase (COX)-2 and enhanced synthesis of prostaglandin E₂ (PGE₂) have been implicated in human endometrial pathologies. To investigate the molecular role of COX-2, the Ishikawa human endometrial epithelial cell line was stably transfected with the pIRES2 vector containing COX-2 cDNA in either the sense or antisense directions. PGE₂ concentrations were significantly elevated in the cells transfected with the COX-2 sense compared with wild-type cells or cells transfected with the antisense cDNA (P < 0.01). Elevated PGE₂ synthesis was associated with enhanced expression and signaling of PGE₂ receptors (EP). cDNA array analysis revealed differential expression of cathepsin D between the COX-2 sense and antisense cells. Cathepsin D RNA and protein expression was 6.7- and 2.1-fold lower in the COX-2 sense compared with COX-2 antisense cells respectively. Cathepsin D is known to cleave plasminogen to the potent antiangiogenic factor angiostatin. To investigate differential angiostatin generation, conditioned media from COX-2 sense, COX-2 antisense and wild-type cells were incubated with plasminogen and subsequently subjected to Western blot analysis. In comparison to wild-type cells, the cleavage of plasminogen to angiostatin was abolished when incubated in COX-2 sense cells conditioned media and elevated when incubated in COX-2 antisense cells conditioned media. Coincubation of plasminogen with the cathepsin D inhibitor pepstatin A inhibited the cleavage of plasminogen to angiostatin in the COX-2 antisense conditioned media. These data demonstrate that COX-2 exerts a negative feedback on the expression of cathepsin D. This in turn reduces the generation of the antiangiogenic factor angiostatin, hence promoting a proangiogenic environment.

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