Galectin-9 suppresses tumor metastasis by blocking adhesion to endothelium and extracellular matrices

Nobumoto, Atsuya; Nagahara, Keiko; Oomizu, Souichi; Katoh, Shigeki; Nishi, Nozomu; Takeshita, Kenjiro; Niki, Toshiro; Tominaga, Akira; Yamauchi, Akira; Hirashima, Mitsuomi

doi:10.1093/glycob/cwn062

Cited by 114 publications

(103 citation statements)

References 46 publications

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“…In addition, we have also seen suppression of VLA-4 (␣-4/␤-1)-VCAM-1 interactions and suppression of metastasis in a murine model of cancer. 44 Thus, the function of Gal-9 could be contextual and different depending on the microenvironment, and the physiologic concentration of Gal-9 in different microenvironments in vivo is not known.…”

Section: Discussionmentioning

confidence: 99%

Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection

Elahi

Niki

Hirashima

et al. 2012

Blood

112

129

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Galectin-9 (Gal-9) is a tandem repeat-type member of the galectin family and is a ligand for T-cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic infection. Studies in autoimmune diseases and chronic viral infections show that Tim-3 is a regulatory molecule that inhibits Th1 type immune responses. Here we show that soluble Gal-9 interacts with Tim-3 expressed on the surface of activated CD4 ؉ T cells and renders them less susceptible to HIV-1 infection and replication. The Gal-9/Tim-3 interaction on activated CD4 ؉ T cells, leads to down-regulation of HIV-1 coreceptors and up-regulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). We suggest that higher expression of Tim-3 during chronic infection has evolved to limit persistent immune activation and associated tissue damage. These data demonstrate a novel mechanism for Gal-9/Tim-3 interactions to induce resistance of activated CD4 ؉ T cells to HIV-1 infection and suggest that Gal-9 may play a role in HIV-1 pathogenesis and could be used as a novel microbicide to prevent HIV-1 infection. (Blood. 2012;119(18):4192-4204) IntroductionProphylactic interventions against HIV-1 acquisition, such as vaccine and microbicide candidates, have not proved efficacious or even enhanced acquisition in previous human clinical trials. 1,2 Even the most promising vaccine to date, which involved a canarypox prime followed by a gp120 protein boost, only showed limited efficacy that waned over time. 3 More effective strategies that block initial HIV-1 acquisition at the site of exposure are required. Interestingly, deletion of 32 base pairs in the ccr5 gene 4 and selective up-regulation of p21 in CD4 ϩ T cells from elite controllers 5 render some individuals naturally resistant to HIV-1 infection. The mechanism(s) responsible for resistance of CD4 ϩ T cells to HIV-1 infection are not well known, but defining them is vital for designing prophylactic interventions.Galectin-9 (Gal-9), a member of the ␤-galactoside-binding animal lectin family, was originally characterized as an eosinophil chemoattractant. 6 Subsequent studies determined that it is a versatile immunomodulator involved in a wide range of biologic activities, such as cell adhesion and migration, proliferation and apoptosis, interaction of host cells with microbial pathogens, regulatory T-cell (Treg) differentiation and function, dendritic cell (DC) maturation, and antimicrobial immunity. 7-13 Gal-9 is expressed by eosinophils, endothelial cells, T lymphocytes, DCs, macrophages, lymphoid cells, Kupffer cells, intestinal epithelial cells, and vascular endothelial cells. 10,[14][15][16][17][18][19] Wide distribution of Gal-9 on host cells demonstrates an important but complex role for this lectin, whose biologic effects are exerted by 2 receptors with distinct, and often opposing effects: TIM-3 (T-cell immunoglobulin [Ig] and mucin domain-containing molecule 3) 20 and cell surface protein disulfide isomerase...

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Section: Discussionmentioning

confidence: 99%

Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection

Elahi

Niki

Hirashima

et al. 2012

Blood

112

129

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“…Association of Gal-1 with ECM proteins causes a direct reduction in leukocyte adhesion, as well as inhibiting T-cell migration through the ECM (He & Baum 2006), whereas Gal-3 localisation with ECM enhances leukocyte adhesion. Gal-9 has also been shown to reduce tumour cell adhesion by preventing binding to ligands on the endothelium and ECM (Nobumoto et al 2008).…”

Section: Actions Of Exogenous Galectin-9mentioning

confidence: 99%

Endogenous galectins and the control of the host inflammatory response

Norling¹,

Perretti²,

Cooper³

2009

Journal of Endocrinology

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A new era of research is being devoted to deciphering endogenous mediators and mechanisms that are in place to resolve the inflammatory response. Accruing evidence indicates that galectins fall into this category of immunoregulatory mediators signifying their use as prospective novel anti-inflammatory agents. The focus of this review is to depict the immunoregulatory bioactivities of three members of the galectin superfamily, Galectin (Gal)-1, Gal-3 and Gal-9.Emphasis is given to the studies investigating the properties of these endogenous lectins. Gal-1, Gal-3 and Gal-9 are emerging as pertinent players in the modulation of acute and chronic inflammatory diseases, autoimmunity and cancer, and thus being increasingly recognised as molecular targets for innovative drug discovery.

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“…[4][5][6][7][8][9][10] Moreover, recent studies have indentified anti-cancer properties of galectin-9 against several cancers. [11][12][13][14][15] In this study, we show the anti-multiple myeloma (MM) activity of a recombinant mutant form of human galectin-9 (hGal9) through the activation of c-Jun NH 2 -terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways, those share crucial roles in the survival and death of myeloma cells. 16 …”

Section: Introductionmentioning

confidence: 99%

Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways

et al. 2010

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Galectins constitute a family of lectins that specifically exhibit the affinity for b-galactosides and modulate various biological events. Galectin-9 is a tandem-repeat type galectin with two carbohydrate recognition domains and has recently been shown to have an anti-proliferative effect on cancer cells. We investigated the effect of recombinant protease-resistant galectin-9 (hGal9) on multiple myeloma (MM). In vitro, hGal9 inhibited the cell proliferation of five myeloma cell lines examined, including a bortezomib-resistant subcell line, with IC 50 between 75.1 and 280.0 nM, and this effect was mediated by the induction of apoptosis with the activation of caspase-8, -9, and -3. hGal9-activated Jun NH 2 -terminal kinase (JNK) and p38 MAPK signaling pathways followed by H2AX phosphorylation. Importantly, the inhibition of either JNK or p38 MAPK partly inhibited the anti-proliferative effect of hGal9, indicating the crucial role of these pathways in the anti-MM effect of hGal9. hGal9 also induced cell death in patient-derived myeloma cells, some with poor-risk factors, such as chromosomal deletion of 13q or translocation t(4;14)(p16;q32). Finally, hGal9 potently inhibited the growth of human myeloma cells xenografted in nude mice. These suggest that hGal9 is a new therapeutic target for MM that may overcome resistance to conventional chemotherapy.

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Galectin-9 suppresses tumor metastasis by blocking adhesion to endothelium and extracellular matrices

Cited by 114 publications

References 46 publications

Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection

Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection

Endogenous galectins and the control of the host inflammatory response

Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways

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