Galectins–potential targets for cancer therapy (original) (raw)
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7. Galectins- potential targets for cancer therapy
Galectins are a family of galactose binding lectins that have become the focus of attention of cancer biologists due to their numerous regulatory roles in normal cellular metabolism and also because of their altered levels in various cancers. They are reportedly similar to several prominent and established modulators of apoptosis. In this review, we present a brief outline of the advancements in the methodology used to detect and identify them and their therapeutic applications in cancer. Their possible interactions with other glycoconjugates are also discussed and a vision for their future use in diagnosis and therapeutics is provided.
Anti-Galectin Compounds as Potential Anti-Cancer Drugs
Galectins form a family of carbohydrate-binding proteins defined by their affinity for b-galactosides containing glycoconjugates. The carbohydrate recognition domain (CRD) is responsible for the specificity of galectins for saccharides. This binding may result in modulated cell proliferation, cell death and cell migration, three processes that are intimately involved in cancer initiation and progression. Galectins can also display protein-protein types of interactions with their binding partners. Certain galectins directly involved in cancer progression seem to be promising targets for the development of novel therapeutic strategies to combat cancer. Indeed, migrating cancer cells resistant to apoptosis still constitute the principal target for the cytotoxic drugs used to treat cancer patients. Reducing the levels of migration in apoptosis-resistant cancer cells can restore certain levels of sensitivity to apoptosis (and so to pro-apoptotic drugs) in restrictedmigration cancer cells. Anti-galectin agents can restrict the levels of migration of several types of cancer cell and should therefore be used in association with cytotoxic drugs to combat metastatic cancer. We provide experimental proof in support of this concept. While the present review focuses on various experimental strategies to impair cancer progression by targeting certain types of galectins, it pays particular attention to glioblastomas, which constitute the ultimate level of malignancy in primary brain tumors. Glioblastomas form the most common type of malignant brain tumor in children and adults, and no glioblastoma patient has been cured to date.
Galectins as Molecular Targets for Therapeutic Intervention
International journal of molecular sciences, 2018
Galectins are a family of small, highly conserved, molecular effectors that mediate various biological processes, including chemotaxis and angiogenesis, and that function by interacting with various cell surface glycoconjugates, usually targeting β-galactoside epitopes. Because of their significant involvement in various biological functions and pathologies, galectins have become a focus of therapeutic discovery for clinical intervention against cancer, among other pathological disorders. In this review, we focus on understanding galectin structure-function relationships, their mechanisms of action on the molecular level, and targeting them for therapeutic intervention against cancer.
Induction of apoptosis in human breast cancer and trophoblast tumor cells by galectin-1
Anticancer research
Galectin-1 (gal-1), a member of the mammalian beta-galactoside-binding proteins, preferentially recognizes Galbeta1-4GlcNAc (LacNAc) sequences of oligosaccharides associated with several cell surface glycoconjugates. As demonstrated histochemically, gal-1 recognizes appropriate glycoepitopes on human breast cancer cells (MCF7) and on human chorionic carcinoma cells (BeWo). Gal-1 is expressed in many malignant and normal tissues. A high level of expression is found in lymphatic organs, which feature high rates of apoptosis. Furthermore, it is known that galectin-1 can initiate T cell apoptosis. In this study, we examined the apoptotic potential of gal-1 in vitro on MCF7 and BeWo cells. After growing both cell lines on chamber-slides for three days, apoptosis was induced by incubation with 30 microg gal-1 per ml serum-free medium for 6, 9 and 20 hours. To avoid false increased rates of apoptosis by deletion of FCS, all approaches were done with and without FCS. Apoptotic cells were de...
Unlocking the secrets of galectins: a challenge at the frontier of glyco-immunology
2000
Over the last decade, we have witnessed an explosion of information regarding the function of glycoconjugates, carbohydrate-binding proteins, and the elucidation of the sugar code. This progress has yielded not only important insights into fundamental areas of glycobiology but has also influenced other fields such as immunology and molecular medicine. A family of galactoside-binding proteins, called galectins, has emerged recently as a novel kind of bioactive molecules with powerful, immunoregulatory functions. Different members of this family have been shown to modulate positively or negatively multiple steps of the inflammatory response, such as cell-matrix interactions, cell trafficking, cell survival, cell-growth regulation, chemotaxis, and proinflammatory cytokine secretion. To introduce a comprehensive overview of these new advances, here we will explore the molecular mechanisms and biochemical pathways involved in these functions. We will also examine the role of these proteins in the modulation of different pathological processes, such as chronic inflammation, autoimmunity, infection, allergic reactions, and tumor spreading. Understanding the intimate mechanisms involved in galectin functions will help to delineate selective and novel strategies for disease intervention and diagnosis. J. Leukoc. Biol. 71: 741-752; 2002.
Breast Cancer Research and Treatment, 2005
Galectins, b-galactoside binding proteins, expressed selectively in human breast carcinoma are attractive targets to employ lectin-aimed therapeutics. We examined b-galactoside binding potency of neoplastic cells using fluorescein-labelled synthetic glycoconjugates as probes for flow cytometry. As a result, surface b-galactoside binding proteins/galectins were discovered on mouse mammary carcinoma cells in vitro and in vivo unlike non-malignant cells from the several tissues; and asialo-GM1 ganglioside carbohydrate part -containing probe was the most specific one. However, in liver and lung metastatic cells galectins seem to be expressed within cytoplasm and/or nuclei. Galectin expression correlated directly with aggressive tumour potential in the A/Sn transplantable model similar to findings in several human breast carcinoma cell lines. However, galectin expression was reduced during tumour progression in more aggressive forms of spontaneous BLRB mammary carcinomas like it was shown for human breast carcinoma specimens. Analysis of the histopathological data led, however, to the conclusion that galectin expression hardly might be a suitable marker of aggressiveness of heterogeneous mammary carcinomas as the observed level of galectin expression is influenced by the amount of the stroma in a tumour sample and/or probably, galectin expression inversely correlates with tumour aggressiveness during the initial and advanced steps of mammary tumour progression. We conclude that surface b-galactoside binding proteins/galectins that are selectively expressed during mouse mammary carcinoma progression, similarly to human breast carcinomas, seem to be proper targets for asialo-GM1-vectored cytotoxics and our mouse model system might be a relevant instrument to further test novel modes of anti-breast cancer therapy.
Cell Death & Differentiation, 2019
Glycosylation and glycan-binding proteins such as galectins play an important role in the control of cell death signaling. Strikingly, very little attention has been given so far to the understanding of the molecular details behind this key regulatory network. Glycans attached to the death receptors such as CD95 and TRAIL-Rs, either alone or in a complex with galectins, might promote or inhibit apoptotic signals. However, we have just started to decode the functions of galectins in the modulation of extrinsic and intrinsic apoptosis. In this work, we have discussed the current understanding of the glycosylation-galectin regulatory network in CD95-as well as TRAIL-R-induced apoptosis and therapeutic strategies based on targeting galectins in cancer. Influence of proapoptotic and antiapoptotic galectins on DR-mediated cell death. • Development of new combinatorial therapies based on targeting galectins and DR pathways.
Galectin-3 as a Potential Target to Prevent Cancer Metastasis
Clinical Medicine Insights: Oncology, 2015
Interactions between two cells or between cell and extracellular matrix mediated by protein-carbohydrate interactions play pivotal roles in modulating various biological processes such as growth regulation, immune function, cancer metastasis, and apoptosis. Galectin-3, a member of the β-galactoside-binding lectin family, is involved in fibrosis as well as cancer progression and metastasis, but the detailed mechanisms of its functions remain elusive. This review discusses its structure, carbohydrate-binding properties, and involvement in various aspects of tumorigenesis and some potential carbohydrate ligands that are currently investigated to block galectin-3 activity.
Cancer Therapy Due to Apoptosis: Galectin-9
Dysregulation of apoptosis is a major hallmark in cancer biology that might equip tumors with a higher malignant potential and chemoresistance. The anti-cancer activities of lectin, defined as a carbohydrate-binding protein that is not an enzyme or antibody, have been investigated for over a century. Recently, galectin-9, which has two distinct carbohydrate recognition domains connected by a linker peptide, was noted to induce apoptosis in thymocytes and immune cells. The apoptosis of these cells contributes to the development and regulation of acquired immunity. Furthermore, human recombinant galectin-9, hG9NC (null), which lacks an entire region of the linker peptide, was designed to resist proteolysis. The hG9NC (null) has demonstrated anti-cancer activities, including inducing apoptosis in hematological, dermatological and gastrointestinal malignancies. In this review, the molecular characteristics, history and apoptosis-inducing potential of galectin-9 are described.
Galectins as Cancer Biomarkers
Cancers, 2010
Galectins are a group of proteins that bind β-galactosides through evolutionarily conserved sequence elements of the carbohydrate recognition domain (CRD). Proteins similar to galectins can be found in very primitive animals such as sponges. Each galectin has an individual carbohydrate binding preference and can be found in cytoplasm as well as in the nucleus. They also can be secreted through non-classical pathways and function extracellularly. Experimental and clinical data demonstrate a correlation between galectin expression and tumor progression and metastasis, and therefore, galectins have the potential to serve as reliable tumor markers. In this review, we describe the expression and role of galectins in different cancers and their clinical applications for diagnostic use.