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(American Journal of Pathology. 2004;164:1925-1933.)
© 2004 American Society for Investigative Pathology

Inhibition of Proprotein Convertases Enhances Cell Migration and Metastases Development of Human Colon Carcinoma Cells in a Rat Model

Mimoun Nejjari*, Virginie Berthet*, Véronique Rigot*, Sullivan Laforest*, Marie-France Jacquier{dagger}, Nabil G. Seidah{ddagger}, Lionel Remy{dagger}, Erik Bruyneel§, Jean-Yves Scoazec{dagger}, Jacques Marvaldi* and José Luis*

From CNRS UMR6032 Faculté de Pharmacie,*Marseille, France; INSERM U45,{dagger}the Faculté de Médecine, Lyon, France; the Laboratoire de Biochimie Neuroendocrinienne,{ddagger}Institut de Recherche Clinique de Montréal, Montréal, Québec, Canada; and Laboratory of Experimental Cancerology,§Ghent University Hospital, Ghent, Belgium

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 {alpha}1-antitrypsin Portland ({alpha}1-PDX, PDX39P cells), a potent convertase inhibitor. We previously reported that these cells bear uncleaved integrin {alpha} subunits and display an altered attachment to vitronectin that is correlated with defects in the intracellular signaling pathways activated by {alpha}vß5 integrin ligation. In this study, we demonstrate that the inhibition of proprotein convertase activity either by overexpression of {alpha}1-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 {alpha}vß5 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-blocking monoclonal antibody (mAb) against the {alpha}v 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 {alpha}v integrins.




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