Matrix Metalloproteinase-9 Promotes Chronic Lymphocytic Leukemia B Cell Survival through Its Hemopexin Domain

Redondo-Munoz, et al. 2010. Cancer cell 17, 160-172

Speaker: Tzu-Hao Yeh (葉子豪)                           Time: 14:10~15:00, Oct 13, 2010

Commentator: Dr. Ai-Li Shiau (蕭璦莉老師)      Place: Room 601

Abstract:

Matrix metalloproteinase (MMP)-9 is a proteolytic enzyme associated with inflammation and cancer development. MMP-9 also plays important roles in migration, invasion and survival of B cell chronic lymphocytic leukemia (B-CLL), and previous studies indicate that these effects involve the proteolytic activity of MMP-9 [1]. The authors recently found that, on the surface of B-CLL cells, MMP-9 binds to α4β1 integrin and CD44v through its hemopexin domain [2]. In this study they further reveal that the MMP-9 binding to cell surface protects B-CLL cells from spontaneous apoptosis. Notably, in this case, MMP-9 promotes B-CLL cell survival through its hemopexin domain but not its proteolytic activity. Treatment with MMP-9 activates a β1 integrin-associated Src family kinase Lyn, which triggers phosphorylation of STAT3 and induces STAT3-mediated transcription of Mcl-1. Thus MMP-9 upregulates the anti-apoptotic protein Mcl-1 that sequesters Bim, suppresses cytochrome c release, and inhibits caspase-3-mediated apoptosis. Furthermore, compared with the counterpart cells from peripheral blood, the B-CLL cells isolated from lymphoid tissues or cocultured with stromal cells show more MMP-9 on the cell surface, higher levels of activated Lyn and Mcl-1, and higher cell viability, suggesting that lymphoid tissues may provide MMP-9 and enhance B-CLL cell survival. On the other hand, though VCAM-1 also interacts with α4β1 and prevents B-CLL apoptosis, it activates PI-3K/Akt and induces another anti-apoptotic protein Bcl-xL, which is completely different from the MMP-9-triggered Lyn-STAT3-Mcl-1 pathway. Therefore, in a proteolysis-independent manner, MMP-9 can function as a ligand to induce a unique signaling pathway and enhance leukemia cell survival.

References:

1.          Ringshausen, et al. Constitutive activation of the MAPkinase p38 is critical for MMP-9 production and survival of B-CLL cells on bone marrow stromal cells. Leukemia 18, 1964–1970 (2004).

2.          Redondo-Munoz, et al. α4β1 integrin and 190 kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells. Blood 112, 169–178 (2008).