On the role of galectin-3 in cancer apoptosis

Galectin-3, a member of the β-galactoside-binding gene family, is a multifunctional protein implicated in a variety of biological functions, including tumor cell adhesion, proliferation, differentiation, angiogenesis, cancer progression and metastasis. Recent studies revealed that intracellular galectin-3 exhibits the activity to suppress drug induced apoptosis and anoikis (apoptosis induced by the loss of cell anchorage) that contribute to cell survival. Resistance to apoptosis is essential for cancer cell survival and plays a role in tumor progression. Conversely, it was recently shown that tumor cells’ secreted galectin-3 induces T-cells’ apoptosis, thus playing a role in the immune escape mechanism during tumor progression through induction of apoptosis of cancer-infiltrating T-cells. This review summarizes recent evidences on the role of galectin-3 as an anti-apoptotic and/or pro-apoptotic factor in various cell types and discusses the recent understanding of the molecular mechanisms of galectin-3 role in apoptosis. We also suggest potential directions for further analyses of this multifunctional protein.

[1]  M. Peter,et al.  The CD95 type I/type II model. , 2003, Seminars in immunology.

[2]  Y. Kloog,et al.  Galectin-3 Augments K-Ras Activation and Triggers a Ras Signal That Attenuates ERK but Not Phosphoinositide 3-Kinase Activity* , 2004, Journal of Biological Chemistry.

[3]  Alexandrina Burlacu,et al.  Regulation of apoptosis by Bcl‐2 family proteins , 2003, Journal of cellular and molecular medicine.

[4]  R. Finley,et al.  Galectin-3 Translocates to the Perinuclear Membranes and Inhibits Cytochrome c Release from the Mitochondria , 2002, The Journal of Biological Chemistry.

[5]  A. Zeiher,et al.  Posttranslational Modification of Bcl-2 Facilitates Its Proteasome-Dependent Degradation: Molecular Characterization of the Involved Signaling Pathway , 2000, Molecular and Cellular Biology.

[6]  H. Pircher,et al.  Beta-galactoside-binding protein secreted by activated T cells inhibits antigen-induced proliferation of T cells. , 1998, European journal of immunology.

[7]  M. Peter,et al.  Two CD95 (APO‐1/Fas) signaling pathways , 1998, The EMBO journal.

[8]  R. Hughes.  Galectins as modulators of cell adhesion. , 2001, Biochimie.

[9]  J. Dennis,et al.  Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation , 2001, Nature.

[10]  T. Yoshii,et al.  Nuclear Export of Phosphorylated Galectin-3 Regulates Its Antiapoptotic Activity in Response to Chemotherapeutic Drugs , 2004, Molecular and Cellular Biology.

[11]  T. Eberlein,et al.  Expression and function of galectin‐3, a β‐galactoside‐binding protein in activated T lymphocytes , 2001, Journal of Leukocyte Biology.

[12]  本城 祐一郎.  Expression of Cytoplasmic Galectin-3 as a Prognostic Marker in Tongue Carcinoma , 2001 .

[13]  T. Sakai,et al.  Nucling mediates apoptosis by inhibiting expression of galectin-3 through interference with nuclear factor kappaB signalling. , 2004, The Biochemical journal.

[14]  R. Hughes,et al.  Determinants in the N-terminal domains of galectin-3 for secretion by a novel pathway circumventing the endoplasmic reticulum-Golgi complex. , 1999, European journal of biochemistry.

[15]  K. Isselbacher,et al.  Mac-2-binding glycoproteins. Putative ligands for a cytosolic beta-galactoside lectin. , 1991, The Journal of biological chemistry.

[16]  L. Baum,et al.  Cutting Edge: CD7 Delivers a Pro-Apoptotic Signal During Galectin-1-Induced T Cell Death1 , 2000, The Journal of Immunology.

[17]  J. Sacchettini,et al.  Multivalent protein-carbohydrate interactions. A new paradigm for supermolecular assembly and signal transduction. , 2001, Biochemistry.

[18]  Kevin C. Haudek,et al.  Nucleocytoplasmic lectins. , 2004, Biochimica et biophysica acta.

[19]  Y. Honjo,et al.  The NH2 terminus of galectin-3 governs cellular compartmentalization and functions in cancer cells. , 1999, Cancer research.

[20]  Etienne Gagnon,et al.  The Phagosome Proteome: Insight into Phagosome Functions , 2001 .

[21]  Stefano Iacobelli,et al.  Galectins and their ligands: amplifiers, silencers or tuners of the inflammatory response? , 2002, Trends in immunology.

[22]  A. Scaloni,et al.  Nuclear localization of Galectin-3 in transformed thyroid cells: a role in transcriptional regulation. , 2003, Biochemical and biophysical research communications.

[23]  S. Mundlos,et al.  Expression of Galectin-3 in Skeletal Tissues Is Controlled by Runx2* , 2003, The Journal of Biological Chemistry.

[24]  Toshihiko Oka,et al.  Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. , 2002, Biochimica et biophysica acta.

[25]  S. Barondes,et al.  Galectins. Structure and function of a large family of animal lectins. , 1994, The Journal of biological chemistry.

[26]  S. Barondes,et al.  Galectins: a family of animal beta-galactoside-binding lectins. , 1994, Cell.

[27]  W. Fung-Leung,et al.  Targeted disruption of the galectin-3 gene results in attenuated peritoneal inflammatory responses. , 2000, The American journal of pathology.

[28]  S. Barondes,et al.  L-29, a soluble lactose-binding lectin, is phosphorylated on serine 6 and serine 12 in vivo and by casein kinase I. , 1993, The Journal of biological chemistry.

[29]  H. Kamata,et al.  Expression of galectin‐3 in neuronally differentiating PC12 cells is regulated both via Ras/MAPK‐dependent and –independent signalling pathways , 2003, Journal of neurochemistry.

[30]  T. Yoshii,et al.  Endogenous Galectin-3 Determines the Routing of CD95 Apoptotic Signaling Pathways , 2004, Cancer Research.

[31]  Riyao Yang,et al.  Expression of galectin-3 modulates T-cell growth and apoptosis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[32]  W. May,et al.  Bcl-2 Phosphorylation Required for Anti-apoptosis Function* , 1997, The Journal of Biological Chemistry.

[33]  John L. Wang,et al.  Intracellular functions of galectins. , 2002, Biochimica et biophysica acta.

[34]  G. Lauc,et al.  Expression of galectin-3 in cells exposed to stress - roles of Jun and NF-κB , 2000, Cellular Physiology and Biochemistry.

[35]  R. Lotan,et al.  Differential expression of galectin-1 and galectin-3 in thyroid tumors. Potential diagnostic implications. , 1995, The American journal of pathology.

[36]  J. L. Wang,et al.  Endogenous lectins from cultured cells: nuclear localization of carbohydrate-binding protein 35 in proliferating 3T3 fibroblasts. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[37]  A. Allione,et al.  Negative cell cycle control of human T cells by β‐galactoside binding protein (βGBP): Induction of programmed cell death in leukaemic cells , 1999, Journal of cellular physiology.

[38]  D. Bredesen,et al.  Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix , 2004, Cell Death and Differentiation.

[39]  R. Lotan,et al.  Expression of a 31‐kDa lactoside‐binding lectin in normal human gastric Mucosa and in primary and metastatic gastric carcinomas , 1994, International journal of cancer.

[40]  H. Inohara,et al.  Galectin-3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family. , 1997, Cancer Research.

[41]  Sucai Dong,et al.  Galectin‐3 stimulates uptake of extracellular Ca2+ in human Jurkat T‐cells , 1996, FEBS letters.

[42]  Michael J. Davis,et al.  Shuttling of galectin-3 between the nucleus and cytoplasm. , 2002, Glycobiology.

[43]  W. Greene,et al.  Human T lymphotropic virus-I infection of human T lymphocytes induces expression of the beta-galactoside-binding lectin, galectin-3. , 1996, American Journal of Pathology.

[44]  R. Bresalier,et al.  Phosphorylation of the β-Galactoside-binding Protein Galectin-3 Modulates Binding to Its Ligands* , 2000, The Journal of Biological Chemistry.

[45]  L. Baum,et al.  Apoptosis of T cells mediated by galectin-1 , 1995, Nature.

[46]  H. Inohara,et al.  Galectin-3 stimulates cell proliferation. , 1998, Experimental cell research.

[47]  A. Raz,et al.  Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells. , 1999, Cancer research.

[48]  John Calvin Reed,et al.  Structure-Function Analysis of Bcl-2 Protein , 1995, The Journal of Biological Chemistry.

[49]  G. Lauc,et al.  Expression of galectin-3 in cells exposed to stress-roles of jun and NF-kappaB. , 2000, Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology.

[50]  R. Lotan,et al.  Induction of differentiation and apoptosis in the prostate cancer cell line LNCaP by sodium butyrate and galectin-1. , 1999, International journal of oncology.

[51]  P. Stewart,et al.  Restricted receptor segregation into membrane microdomains occurs on human T cells during apoptosis induced by galectin-1. , 1999, Journal of immunology.

[52]  J. Jessup,et al.  Galectin-3 protects human breast carcinoma cells against nitric oxide-induced apoptosis: implication of galectin-3 function during metastasis. , 2001, The American journal of pathology.

[53]  L. Baum,et al.  Galectin-1, an Endogenous Lectin Produced by Thymic Epithelial Cells, Induces Apoptosis of Human Thymocytes , 1997, The Journal of experimental medicine.

[54]  T. Yoshii,et al.  Galectin-3 Phosphorylation Is Required for Its Anti-apoptotic Function and Cell Cycle Arrest* , 2002, The Journal of Biological Chemistry.

[55]  V. Castronovo,et al.  Dual activities of galectin-3 in human prostate cancer: tumor suppression of nuclear galectin-3 vs tumor promotion of cytoplasmic galectin-3 , 2004, Oncogene.

[56]  J. Ochieng,et al.  Galectin-3 mediates the endocytosis of β-1 integrins by breast carcinoma cells , 2001 .

[57]  Riyao Yang,et al.  Role of the carboxyl-terminal lectin domain in self-association of galectin-3. , 1998, Biochemistry.

[58]  L. Pellegrini,et al.  Cloning of AIP1, a Novel Protein That Associates with the Apoptosis-linked Gene ALG-2 in a Ca2+-dependent Reaction* , 1999, The Journal of Biological Chemistry.

[59]  J. Ochieng,et al.  Galectin-3 mediates the endocytosis of beta-1 integrins by breast carcinoma cells. , 2001, Biochemical and biophysical research communications.

[60]  A. Nichols,et al.  Alix, a novel mouse protein undergoing calcium-dependent interaction with the apoptosis-linked-gene 2 (ALG-2) protein , 1999, Cell Death and Differentiation.

[61]  N. Tinari,et al.  Concentrations of galectin-3 in the sera of normal controls and cancer patients. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[62]  R. Hughes.  Secretion of the galectin family of mammalian carbohydrate-binding proteins. , 1999, Biochimica et biophysica acta.

[63]  T. Yoshii,et al.  CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis. , 2003, Cancer research.

[64]  R. Lotan,et al.  Carcinoembryonic antigen and other glycoconjugates act as ligands for galectin-3 in human colon carcinoma cells. , 1995, Cancer research.

[65]  A. Raz,et al.  Galectin-3 enhances cyclin D1 promoter activity through SP1 and a cAMP-responsive element in human breast epithelial cells , 2002, Oncogene.

[66]  Y. Takenaka,et al.  Galectin-3 and metastasis , 2004, Glycoconjugate Journal.

[67]  N. Tinari,et al.  Galectin‐3 overexpression protects from apoptosis by improving cell adhesion properties , 2000, International journal of cancer.