Inhibition of proprotein convertases enhances cell migration and metastases development of human colon carcinoma cells in a rat model

Although proprotein convertases are involved in tumor development, nothing is known about their role in metastatic dissemination. To investigate the involvement of convertase inhibition, we used human colon carcinoma cells overexpressing α1-antitrypsin Portland (α1-PDX, PDX39P cells), a potent convertase inhibitor. We previously reported that these cells bear uncleaved integrin α subunits and display an altered attachment to vitronectin that is correlated with defects in the intracellular signaling pathways activated by αvβ5 integrin ligation. In this study, we demonstrate that the inhibition of proprotein convertase activity either by overexpression of α1-PDX or with the synthetic inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone (dec-RVKR-cmk) led to a significant increase in cell migration supported by the αvβ5 integrin. A collagen gel invasion assay showed that PDX39P cells also displayed an invasive ability, contrary to control cells. Moreover, when injected to immunosuppressed newborn rats, PDX39P cells were highly invasive, as they induce 10 times more metastases than mock-transfected cells. In addition, the aggressiveness of PDX39P cells can be greatly reduced by a function-blockidng monoclonal antibody (mAb) against the αv subunit. It thus seems that inhibition of proprotein convertases enhances the in vivo invasiveness of colon tumor cells likely due to an increase in cell migration mediated by αv integrins.