The ADAMTS12 metalloproteinase exhibits anti-tumorigenic properties through modulation of the Ras-dependent ERK signalling pathway.
Members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteolytic enzymes are implicated in a variety of physiological processes, such as collagen maturation, organogenesis, angiogenesis, reproduction and inflammation. Moreover, deficiency or overexpression of certain ADAMTS proteins is directly involved in serious human diseases, including cancer. However, the functional roles of other family members, such as ADAMTS12, remain unknown. Here, by using different in vitro and in vivo approaches, we have evaluated the possible role of ADAMTS12 in the development and progression of cancer. First, we show that expression of ADAMTS12 in Madin-Darby canine kidney (MDCK) cells prevents the tumorigenic effects of hepatocyte growth factor (HGF) by blocking the activation of the Ras-MAPK signalling pathway and that this regulation involves the thrombospondin domains of the metalloproteinase. We also show that addition of recombinant human ADAMTS12 to bovine aortic endothelial cells (BAE-1 cells) abolishes their ability to form tubules upon stimulation with vascular endothelial growth factor (VEGF). Additionally, tumours induced in immunodeficient SCID mice injected with A549 cells overexpressing ADAMTS12 show a remarkable growth deficiency in comparison with tumours formed in animals injected with parental A549 cells. Overall, our data suggest that ADAMTS12 confers tumour-protective functions upon cells that produce this proteolytic enzyme.
Llamazares
María
M
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncologia, Universidad de Oviedo, 33006-Oviedo, Asturias, Spain.
Obaya
Alvaro J
AJ
Moncada-Pazos
Angela
A
Heljasvaara
Ritva
R
Espada
Jesús
J
López-Otín
Carlos
C
Cal
Santiago
S
D051722:ADAM Proteins / Q000737:chemistry / Q000378:metabolism*; D000071096:ADAMTS Proteins; D000818:Animals; D002417:Cattle; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000473:pathology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D020928:Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C496252:ADAMTS12 protein, human; D018631:ras Proteins