TY - JOUR
T1 - Inhibition of proprotein convertases enhances cell migration and metastases development of human colon carcinoma cells in a rat model
AU - Nejjari, Mimoun
AU - Berthet, Virginie
AU - Rigot, Véronique
AU - Laforest, Sullivan
AU - Jacquier, Marie France
AU - Seidah, Nabil G.
AU - Remy, Lionel
AU - Bruyneel, Erik
AU - Scoazec, Jean Yves
AU - Marvaldi, Jacques
AU - Luis, José
N1 - Funding Information:
Supported in part by grants from the ARC (Association pour la Recherche sur le Cancer), the GEFLUC (Groupement des Entreprises Françaises dans la Lutte contre le Cancer) the Ligue Nationale contre le Cancer and the INSERM (Institut National de Santé et de Recherche Médicale), and by a CIHR grant MGP-44363 to N.G.S .
PY - 2004/1/1
Y1 - 2004/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=2442664240&partnerID=8YFLogxK
U2 - 10.1016/S0002-9440(10)63753-4
DO - 10.1016/S0002-9440(10)63753-4
M3 - Article
C2 - 15161629
AN - SCOPUS:2442664240
SN - 0002-9440
VL - 164
SP - 1925
EP - 1933
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -