Disease relevance of LGALS8

• Screening a human LNCaP prostate cancer cDNA expression library with the Pro 1.5 mAb identifies a gene, prostate carcinoma tumor antigen-1 (PCTA-1) [1].
• Primer pairs within the 3' untranslated region of PCTA-1 and reverse transcription-PCR demonstrate selective expression of PCTA-1 by prostate carcinomas versus normal prostate and benign prostatic hypertrophy [1].
• Grafting the four experimental human colon cancer models onto nude mice enabled us to show that the immunohistochemical expression of galectin-8 was inversely related to tumour growth rate [2].
• It appears that PCTA-1 expression is almost ubiquitous in normal human tissues and could alter in specific contexts such as transformation or metastasis [3].
• Experiments carried out by reverse transcriptase-polymerase chain reaction show that the levels of expression of these five galectin-8 isoforms are variable during the culture time in SK-MES-1, a human lung squamous carcinoma cell line [4].

High impact information on LGALS8

• After screening 3 x 10(6) clones from 3 different cDNA libraries, 15 tumor antigens were identified, including cytokeratin 2-8, glutamyl-prolyl-tRNA synthetase, complement C3, galectin 8, and serine/threonine-rich protein kinase 1 [5].
• Galectin-3, galectin-1, and to a lesser extent galectin-8, markedly stimulate glioblastoma cell migration in vitro [6].
• Indeed, galectin-8-induced apoptosis was 2-fold higher in HTC (p21-null) cells when compared with parental HTC cells [7].
• Cyclin-dependent kinase inhibitors and JNK act as molecular switches, regulating the choice between growth arrest and apoptosis induced by galectin-8 [7].
• These effects cannot be attributed to interference with cell adhesion but can be attributed to a 4-5-fold increase in the cellular content of the cyclin-dependent kinase inhibitor p21, which was already evident following a 4-h incubation of H1299 cells with galectin-8 [7].

Chemical compound and disease context of LGALS8

• In contrast, diltiazem 180 mg per day was reported more recently to significantly reduce restenosis, and high-dose verapamil treatment was similarly successful in a subgroup of patients with stable angina pectoris at the time of primary successful PCTA [8].
• The aim was also to evaluate the possible protective effects of calcium antagonists (nisoldipine) and nitrates against myocardial stunning in patients with coronary artery disease undergoing routine coronary angioplasty (PCTA) with prolonged inflation [9].

Biological context of LGALS8

• Studies show that the LGALS8 gene encodes for almost seven mRNAs by alternative splicing pathways and various polyadenylation sites [10].
• Here we demonstrated that soluble galectin-8 inhibits cell cycle progression and induces growth arrest [7].
• These results implicate galectin-8 as a modulator of cellular growth through up-regulation of p21 [7].
• The role of galectin-8 (and its neutralising antibody) in cell migration was investigated in HCT-15, LoVo, CoLo201, and DLD-1 cell lines [2].
• We propose that galectin-8 is an integrin binding-protein that interacts to a different extent with several, but not all members of the integrin family [11].

Anatomical context of LGALS8

• Microsequencing and western immunoblotting revealed that (alpha)(3)(beta)(1 )integrin derived from 1299 as well as other cells (e.g. HeLa and human endothelial cells) is a major galectin-8 binding-protein [11].
• These results indicate that Gal-8 constitutes a novel extracellular stimulus for T cells, able to bind specific beta1 integrins and to trigger signaling pathways conducive to cell spreading [12].
• Galectin-8 binds specific beta1 integrins and induces polarized spreading highlighted by asymmetric lamellipodia in Jurkat T cells [12].
• Strikingly, Gal-8 was also a strong stimulus on Jurkat cells in suspension, triggering ERK1/2 activation that in most adherent cells is instead dependent on cell attachment [12].
• We investigated the effects of galectin-8 on neutrophil function [13].

Associations of LGALS8 with chemical compounds

• When p21 expression was inhibited by cycloheximide, galectin-8 directed the cells toward apoptosis, which involves induction of poly(ADP-ribose) polymerase cleavage [7].
• Galectin-8 also interacts with other members of the integrin family, like (alpha)(6)(beta)(1 )integrins [11].
• Pretreatment of the cells with Mn(2+), which increases the affinity of integrins for their ligands, abolished the inhibitory effects of galectin-8 [11].
• Galectin-8 had much higher affinity for 3'-O-sulfated or 3'-O-sialylated lactose and a Lewis x-containing glycan than for oligosaccharides terminating in Galbeta1-->3/4GlcNAc [14].
• Cell adhesion is potentiated in the presence of Mn(2+), whereas it is interrupted in the presence of soluble galectin-8, integrin beta(1) inhibitory antibodies, EDTA, or thiodigalactoside but not by RGD peptides [15].
• In glycan microarray analyses, each CRD of Gal-8 showed different binding, with Gal-8N recognizing sulfated and sialylated glycans and Gal-8C recognizing blood group antigens and polyLacNAc glycans [16].

Physical interactions of LGALS8

• Gal-8-induced Rac-1 activation and binding to alpha1 and alpha5 integrins have not been described in any other cellular system [12].
• Affinity purification of galectin-interacting proteins from solubilized neutrophil membrane revealed that N-terminal carbohydrate recognition domain (CRD) of galectin-8 bound promatrix metalloproteinase-9 (proMMP-9), and C-terminal CRD bound integrin alphaM/CD11b and proMMP-9 [13].

Other interactions of LGALS8

• Galectin-8, a mammalian beta-galactoside binding lectin, functions as an extracellular matrix protein that forms high affinity interactions with integrins [7].
• The inhibitory effects of galectin-8 were specific and were not mimicked by plant lectins or other galectins (galectin-1 and galectin-3) [11].
• In addition, we found that patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disorder, produce Gal-8 autoantibodies that impede both its binding to integrins and cell adhesion [12].
• MMP-3-mediated processing of proMMP-9 was accelerated by galectin-8, and this effect was inhibited by lactose [13].
• In contrast, when present in excess as a soluble ligand, galectin-8 (like fibronectin) forms a complex with integrins that negatively regulates cell adhesion [15].

Analytical, diagnostic and therapeutic context of LGALS8

• CONCLUSIONS: Expression of galectin-8 correlated with malignancy development, with suppressor activity, as shown by analysis of clinical samples and xenografts [2].
• The presence of galectin-8 mRNA in the four human colon cancer cell lines was examined by reverse transcriptase-polymerase chain reaction [2].
• Furthermore, immunoprecipitation and immunohistochemical studies suggested that endogenous galectin-8, secreted from 1299 cells, forms complexes with (alpha)(3)(beta)(1) integrins expressed on the surface of 1299 cells [11].
• In vitro galectin-8 mediated effects (and the influence of its neutralising antibody) on migration levels of living HCT-15, LoVo, CoLo201, and DLD-1 cells were quantitatively determined by computer assisted phase contrast microscopy [2].
• Affinity chromatography over immobilized galectin-8 indicated that few membrane proteins interacted with galectin-8 in a sugar-dependent manner [11].

References