Inhibition of galectins in cancer: Biological challenges for their clinical application (original) (raw)

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.

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.

Galectins–potential targets for cancer therapy

Cancer letters, 2007

Impact of Galectins in Resistance to Anticancer Therapies

Clinical Cancer Research, 2020

Galectins are an endogenous family of β-galactoside-binding proteins that play complex and multifaceted roles at various stages of cancer progression, including modulation of tumor cell proliferation, signaling, adhesion, migration, invasion, epithelial–mesenchymal transition, angiogenesis, and immune escape. Recently, galectins have been implicated as major therapeutic determinants that confer sensitivity or resistance to a wide range of anticancer modalities including chemotherapy, radiotherapy, targeted therapies, antiangiogenic therapies, and immunotherapies. Here, we present an integrated approach to the pleiotropic functions of galectins and discuss their emerging roles with respect to mechanisms of resistance or sensitivity to anticancer therapies. Taken together, these findings suggest that targeting galectins and/or their glycosylated ligands may help to overcome resistance and to increase the clinical efficacy of anticancer strategies.

Galectins as pivotal components in oncogenesis and immune exclusion in human malignancies

Galectins as pivotal components in oncogenesis and immune exclusion in human malignancies, 2023

Galectins are galactoside-binding proteins, exerting numerous functions inside and outside the cell, particularly conferring adaptation to stress factors. For most of them, aberrant expression profiles have been reported in the context of cancer. Albeit not being oncogenic drivers, galectins can be harnessed to exacerbate the malignant phenotype. Their impact on disease establishment and progression is not limited to making cancer cells resistant to apoptosis, but is prominent in the context of the tumor microenvironment, where it fosters angiogenesis, immune escape and exclusion. This review focuses mainly on Gal-1, Gal-3 and Gal-9 for which the involvement in cancer biology is best known. It presents the types of galectin dysregulations, attempts to explain the mechanisms behind them and analyzes the different ways in which they favor tumour growth. In an era where tumour resistance to immunotherapy appears as a major challenge, we highlight the crucial immunosuppressive roles of galectins and the potential therapeutic benefits of combinatorial approaches including galectin inhibition.

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 dysregulation: A way for cancer cells to invade and pervade

Oncology Research

Galectins are sticky molecules that bind to β-galactoside. Their interactions render them essential players in many cellular processes. The imbalance of galectin expression was reported in many diseases. In cancer, galectins interact with the extracellular matrix, evade the immune system, and potentially have broad interactions with blood components. In the last ten years, since 2010, we did focus on galectin research in different cancer types. Our findings showed an interaction between cancer cells and erythrocytes via galectin-4. Moreover, we found that upregulation of galectins was associated with lymph node metastasis in ovarian cancers. Hence, with this, we shortly review some important aspects of galectins and their potential importance in more profound understanding of cancer progression and the field of cancer biomarkers. Galectins are Potentially Supporting Cancer Cells to Invade and Metastasize via Interaction with Blood Components In 2017, an interaction between cancer cells and erythrocytes was reported and interpreted by galectin-4 interaction with the blood group antigen (Fig. 1). Displacement of galectin-4 to attachment points of cancer cells and erythrocytes was noticed. Also, we found in this article, a co-localization of galectin-4 and blood group antigen was seen using double fluorescent immunostaining. Moreover, a morphological deformation of red blood cells was seen to be associated with this interaction [1]. In this model, interacting cells were dividing without the presence of an attachment surface. In addition, developing lamellipodia/filopodia was noticed after interactions [1]. According to the structure of galectins, all surface/secreted galectins might interact with erythrocytes. Thus, many questions have been raised regarding the dysregulation of galectins in cancer. For instance, is the upregulation of galectins related to invasive cancers or lymph node metastasis? Thus, our group sought mRNA expression in many types of cancers, including AML [2,3], ovarian [4], endometrial, and breast (unpublished). Consistent with our hypothesis, in ovarian cancer, we found that galectin-9 might be a potential marker for lymph node metastasis [4]. Supportive Biological Evidence and Functions Related to Galectins and Cancer Galectin family Galectins are protein family that have a high affinity for binding to β-galactoside like N-acetyllactosamine via Nlinked or O-linked glycosylation. Galectins are a structurally associated family containing at least one carbohydrate recognition domain (CRD) [5,6]. The CRD of this family is folded into a β-sandwich structure consisting of two stretched antiparallel β-sheets. Galectin's ligand binds to the groove formed by β-sandwich [7]. Up to now, there are sixteen members of the galectins family. Depending on their structure, galectins are categorized into three different types: prototype, tandem repeat or chimera. Prototypical galectins (LGALS1, 2, 5, 7, 10, 11, 13, 14 and 15) contain one CRD that can dimerize. Tandem galectins (LGALS4, 6, 8, 9, and 12) are at least two CRD linked together by a small peptide domain. Galecin-3 is the only member that contains one CRD linked to the N-terminal non-lectin domain [8,9]. These structural aspects render them a key players in several cellular processes, as shown in Fig. 2. Subcellular localization Galectins display a wide range of distribution (Table 1

Varied expression and localization of multiple galectins in different cancer cell lines

Oncology Reports, 2008

Galectins play a key role in oncogenic processes. Although several galectins are known, their relative expression at the mRNA and protein levels, the subcellular localization, and their relationship to the oncogenic manifestation remains unclear. Herein we report a comprehensive characterization of the expression of major galectins in human breast cancer (drug-sensitive MCF-7 and drug-resistant MCF-7/Adr R), colon cancer (HCT-116 and HT-29), and glioma (T98G) cell lines, as these cells are common model systems for studying oncogenic processes. The expected ~14.5 kDa galectin-1, predominantly cytosolic, was detected in the cancer and normal cell lines. Notably, two different molecular forms of galectin-1 with molecular masses of ~13.5 and 15 kDa were detected in T98G cells, the latter being in the extracellular medium, perhaps a result of post-translational processing. Immunocytochemistry indicated that the extracellular galectin-1 bound to the cell surface was punctated in appearance, suggesting that it was bound to specific receptors. Immunohistological studies indicated that metastasizing carcinomas express high levels of galectin-1. On the other hand, galectin-3 was readily detectable in all cancer cell lines but undetectable in normal cell lines, indicating that galectin-3 is a cancer-specific biomarker protein. Galectin-3 was a cytosolic protein but was not detected in the extracellular medium, indicating that cancer cells do not secrete this galectin. Finally, despite the RT-PCR analysis suggesting the presence of two transcripts of galectin-8 in all cancer cell lines, the corresponding ~36 kDa protein was only detectable in the nuclear and cytosolic fractions upon cell fractionation. Notably, a different molecular form of galectin-8 of ~18 kDa was immunoprecipitated from the extracellular media, suggesting that the secreted galectin-8 undergoes post-translational processing. These results highlight the expression of galectins in different molecular forms in cancers, warranting caution in interpreting the results of functional studies of individual galectins, particularly because these proteins function redundantly in cancer pathways.

Extracellular and intracellular small-molecule galectin-3 inhibitors

Scientific Reports, 2019

Galectin-3 is a carbohydrate binding protein which has important roles in cancer and immunity. Potent galectin-3 inhibitors have been synthesized, for experimental purposes and potential clinical use. As galectin-3 is implicated in both intra-and extracellular activities, permeability of galectin-3 inhibitors is an important parameter determining biological effects. We compared the cellular uptake of galectin-3 inhibitors and their potency in the intracellular or extracellular space. The inhibitors differed in their polar surface area (PSA), but had similar affinities for galectin-3. Using a well-established permeability assay, we confirmed that the uptake was significantly higher for the inhibitor with the lowest PSA, as expected. To analyze intracellular activity of the inhibitors, we developed a novel assay based on galectin-3 accumulation around damaged intracellular vesicles. The results show striking differences between the inhibitors intracellular potency, correlating with their PSAs. To test extracellular activity of the inhibitors, we analyzed their potency to block binding of galectin-3 to cell surfaces. All inhibitors were equally able to block galectin-3 binding to cells and this was proportional to their affinity for galectin-3. These inhibitors may serve as useful tools in exploring biological roles of galectin-3 and may further our understanding of intracellular versus extracellular roles of galectin-3. The galectin family of carbohydrate binding proteins have gained increasing interest as therapeutic targets in several diseases, such as chronic inflammation and cancer 1-4. Galectins are soluble proteins synthesized on free ribosomes in the cytosol. Even though they lack the classical characteristics of secreted proteins, they are rapidly translocated to the extracellular space through a yet unknown pathway 5. Once in the extracellular environment, the galectins are exposed to a large variety of glycan structures, where they recognize and bind specific β-galactosides. As some galectins are able to form multivalent structures or are multivalent in nature, they are able to cross-link glycoconjugates and form lattices. Formation of galectin/glycoconjugate lattices on the plasma membrane has been observed to influence the expression time, localization, and activity of several cell surface receptors, thus influencing numerous biological functions such as cell signaling, cell migration, and cell adherence 5,6. Furthermore, galectins can quickly (within minutes) be recycled back to the inside of cells trough the endocytic pathway, regulating sorting of both soluble and membrane bound glycoconjugates 5,7. Apart from the extracellular activities of the galectin family, mediated through glycan binding, galectins also play important roles in the intracellular compartments. Several studies have reported that galectins may influence cell signaling by interacting with signaling proteins in the cytosol, e.g. RAS proteins and β-catenin, and RNA splicing through binding of components of the spliceosome complex in the nucleus 8-12. As complex glycans are not found in the intracellular compartment, these activities are most likely mediated trough protein-protein interactions. Interestingly, however, several of these reported intracellular activates are inhibited by molecules interacting with the galectin carbohydrate binding site, such as lactose 8,10,13. Additionally, galectins play an important role at the interface between the cytosolic and intravesicular compartments by monitoring the integrity of vesicular membranes. It is now well established that several galectins (e.g. galectin-3 and-8 in particular) accumulate around disrupted vesicles by binding to exposed glycan structures and induce clearance of the damaged organelles by selective autophagy 14-20. The diverse roles of the galectins on a cellular level have consequences for several physiological

Inhibition of galectins in cancer: Biological challenges for their clinical application (original) (raw)

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