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 alpha1-antitrypsin Portland (alpha1-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 alphavbeta5 integrin ligation. In this study, we demonstrate that the inhibition of proprotein convertase activity either by overexpression of alpha1-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 alphavbeta5 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 alphav 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 alphav integrins.
Nejjari
Mimoun
M
CNRS UMR6032 Faculté de Pharmacie, Marseille, France.
Berthet
Virginie
V
Rigot
Véronique
V
Laforest
Sullivan
S
Jacquier
Marie-France
MF
Seidah
Nabil G
NG
Remy
Lionel
L
Bruyneel
Erik
E
Scoazec
Jean-Yves
JY
Marvaldi
Jacques
J
Luis
José
J
D000230:Adenocarcinoma / Q000473:pathology / Q000556:secondary; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003094:Collagen; D003110:Colonic Neoplasms / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology* / Q000517:prevention & control; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000378:metabolism
D011994:Recombinant Proteins; D000515:alpha 1-Antitrypsin; D003094:Collagen; D043484:Proprotein Convertases