A catalytically inactive gelatinase B/MMP-9 mutant impairs homing of chronic lymphocytic leukemia cells by altering migration regulatory pathways

We previously showed that MMP-9 overexpression impairs migration of primary CLL cells and MEC-1 cells transfected with MMP-9. To determine the contribution of non-proteolytic activities to this effect we generated MEC-1 transfectants stably expressing catalytically inactive MMP-9MutE (MMP-9MutE-cell...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2018-01, Vol.495 (1), p.124-130
Main Authors: Bailón, Elvira, Aguilera-Montilla, Noemí, Gutiérrez-González, Alejandra, Ugarte-Berzal, Estefanía, Van den Steen, Philippe E., Opdenakker, Ghislain, García-Marco, José A., García-Pardo, Angeles
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
BONE MARROW
Cell migration
CLL
Homing
LEUKEMIA
MICE
Non-proteolytic MMP-9
Signaling pathways
SPLEEN
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Summary:We previously showed that MMP-9 overexpression impairs migration of primary CLL cells and MEC-1 cells transfected with MMP-9. To determine the contribution of non-proteolytic activities to this effect we generated MEC-1 transfectants stably expressing catalytically inactive MMP-9MutE (MMP-9MutE-cells). In xenograft models in mice, MMP-9MutE-cells showed impaired homing to spleen and bone marrow, compared to cells transfected with empty vector (Mock-cells). In vitro transendothelial and random migration of MMP-9MutE-cells were also reduced. Biochemical analyses indicated that RhoAGTPase and p-Akt were not downregulated by MMP-9MutE, at difference with MMP-9. However, MMP-9MutE-cells or primary cells incubated with MMP-9MutE had significantly reduced p-ERK and increased PTEN, accounting for the impaired migration. Our results emphasize the role of non-proteolytic MMP-9 functions contributing to CLL progression. •MMP-9MutE (non-catalytic) impairs migration and in vivo homing of CLL cells.•MMP-9MutE-impaired migration does not involve RhoAGTPase activity.•MMP-9MutE downregulates p-ERK and increases PTEN expression.•MMP-9MutE affects signaling pathways regulating CLL cell migration.•MMP-9 contributes to CLL progression by catalytic and non-catalytic activities.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2017.10.129