Matrix metalloproteinase-9 interplays with the IGFBP2-IGFII complex to promote cell growth and motility in astrocytomas.
Insulin-like growth factor II (IGFII) acts as a potent mitogen for several tumor types and has been reported to positively influence astrocytoma cell growth and motility. In the central nervous system, IGFII bioavailability is mainly modulated by insulin-like growth factor binding protein 2 (IGFBP2), which sequestrates IGFII and therefore prevents its interaction with the type-1 IGF receptor (IGF-IR). Proteolysis of IGFBP2 is the predominant mechanism recognized to reduce the binding affinity of IGFBP2 for IGFII, thus favoring dissociation of IGFII from the IGFBP2-IGFII complex. It is known that certain proteases involved in astrocytoma malignancy, such as matrix metalloproteinase-7 (MMP-7), plasmin, and cathepsin D, are able to proteolyze IGFBP2 in vitro. The present study aims to investigate whether other proteases expressed by astrocytomas, specifically MMP-2, MMP-9, and membrane-type 1 matrix metalloprotease (MT1-MMP), are able to proteolyze the IGFBP2-IGFII complex. Our results show the following: (i) MMP-9 proteolyzes the IGFBP2-IGFII complex in vitro, while MMP-2 and MT1-MMP do not; (ii) this MMP-9-induced IGFBP2-IGFII complex proteolysis releases free IGFII, which contributes to enhance the motility and the growth of LN229 astrocytoma cells. Furthermore, this study also highlights that the formation of the IGFBP2-IGFII complex inhibits IGFBP2's cell motility promoting effect by reducing the pool of free IGFBP2. In conclusion, MMP-9-induced IGFBP2 proteolysis may be regarded as an important post-translational event involved in astrocytoma aggressiveness. These new findings support drug targeting of MMP-9 as an interesting approach in the treatment of astrocytoma.
Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Sandrine
S
Rorive
Alix
A
Berton
Nicky
N
D'haene
Constantin Nicolae
CN
Takacs
Olivier
O
Debeir
Christine
C
Decaestecker
Isabelle
I
Salmon
D001254:Astrocytoma / Q000378:metabolism* / Q000503:physiopathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D015536:Down-Regulation / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D046911:Macromolecular Substances / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D010447:Peptide Hydrolases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology
C035170:IGF2 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D046911:Macromolecular Substances; D007335:Insulin-Like Growth Factor II; D010447:Peptide Hydrolases; D020780:Matrix Metalloproteinase 9