Galectins Potential Targes For Cancer Therapy


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Galectins Potential Targes For Cancer Therapy

  1. 1. Cancer Letters 253 (2007) 25–33 Mini-review Galectins – Potential targets for cancer therapy Syed Saif Hasan a, Ghulam Md. Ashraf b, Naheed Banu b,* a Molecular Biology Unit, National Centre for Cell Science, University of Pune Campus, Ganeshkhind, Pune 411007, Maharashtra, India b Department of Biochemistry, Faculty of Life Sciences, A.M. University, Aligarh 202002, UP, India Received 30 October 2006; received in revised form 29 November 2006; accepted 29 November 2006 Abstract 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 can- cer. Their possible interactions with other glycoconjugates are also discussed and a vision for their future use in diagnosis and therapeutics is provided. Ó 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Galectins; Cancer; Metastasis; Glycoconjugates; Detection; Inhibition; Therapy 1. Introduction to galectins processes, be they normal such as fertilization, growth and differentiation or pathological such as Structure-specific recognition between cognate infection and cancer. Lectins which are proteins of biomolecules is being increasingly proved to be the non-immune origin that recognize and bind corre- initiator of events that mark major biological sponding sugar residues without altering the struc- ture of the latter [1,2] play a major role in biological recognition. Herman Stillmark published Abbreviations: CRD, carbohydrate recognition domain; SMN, one of the first reports of these molecules in 1888 survival of motor neurons; TTF-1, thyroid specific transcription when he discovered an agglutinin of erythrocytes in factor-1; Rb, retinoblastoma; PCNA, proliferating cell nuclear antigen; RCF, replication factor C; ECM, extracellular matrix; extracts of castor beans [3]. The main interest in plant PCTA-1, prostate carcinoma tumor antigen-1; GM3, N-acetylne- lectins lay in their potential use as biological reagents uraminosyl-(a2-3)-galactosyl-(b1-4)-glucosylceramide; RT-PCR, that could bind specific cell surface glycoconjugates. reverse transcriptase polymerase chain reaction; ELISA, enzyme- With the development of mammalian cell culture linked immunosorbant assay; Glyc, carbohydrate moiety; PAA, techniques, lectins were used to study changes in gly- polyacrylamide; Fluo, fluorescein based label; LacNAc, galacto- syl b (1–4) N-acetyl glucosylamine; Tyr, tyrosine. coconjugates on the surface of cancer cells, and as * Corresponding author. Tel.: +91 9897000193. mitogens that could induce the proliferation of E-mail address: (N. Banu). lymphocytes. One of the members of this group of 0304-3835/$ - see front matter Ó 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2006.11.030
  2. 2. 26 S.S. Hasan et al. / Cancer Letters 253 (2007) 25–33 proteins is the galectins. Identified as N-acetyllactos- metastasis [33,34] and apoptosis [35–37] are modu- amine binding proteins in the electric eel [4], they lated by the interactions of these molecules. The have been found in all taxa of the living world from underlying principle of all these functions is carbo- sponges to humans [5–7]. They were formally classi- hydrate recognition. Galectin-1 has been shown to fied into a family based on their characteristic feature promote growth at low concentrations and to inhib- of possessing a carbohydrate recognition domain it cellular growth at higher levels, under in vitro con- and affinity for b-galactosides, besides sharing cer- ditions [30]. Moreover, their functions include the tain conserved sequence elements that require a regulation of gene expression. Along with gemin-4, reducing environment for action but no divalent ions galectin-1 and À3 act as pre-mRNA splicing factors [5]. Sequencing of many proteins that exhibited the in the SMN splicing complex for the gene whose property of binding b-galactosides revealed extensive aberrant expression is implicated in spinal muscular sequence similarity, in addition to the already recog- atrophy [38,39]. It is, therefore, imperative that the nized capacity to bind specific sugars [8]. expression of these molecules be tightly regulated as is validated by the observation of their varying 1.1. Structural features of galectins levels in specific stages of development [31]. Galectin expression has been found to be sensitive to viral The CRD consists of 5–6 anti-parallel b-pleated infections [40], tumor suppressor genes [41] and sheets that form an extended sandwich with a typ- inflammatory agents [42]. In addition, the use of a ical jellyroll topology and is around 135 amino differentiating agent - sodium butyrate was shown acids long [9]. The core sequence of this domain lies to modulate the expression of galectin-1 by tran- between the 30th and 90th residues and is encoded scriptional regulation and histone deacetylation in by a single exon [8]. The number and arrangement human head and neck squamous carcinoma cells of the CRDs can vary and has been used as a basis [43] but other than this study, not much advance- of their classification [10]. The proto-type galectins ment has been made in this direction. Their unusual are non-covalent homodimers of two identical secretion mechanism has also been an enigma. CRDs that are able to cross-link ligands on cell sur- Although they lack a specific secretion signal faces and extracellular matrix [11] and include Cae- [28,44], galectins are secreted by a mechanism that norhabditis elegans 16 kDa galectin [16], frog is not yet understood properly. It has been suggest- galectins [17], electrolectin [18], chicken isolectins ed that some transmembrane carriers export galec- C-14 and C-16 [19,20], galectins-1 [7,12], À2 [13], tin-1 out of the cells by a mechanism similar to À5 [14], À7 [15], À10 [10], À11 [10], À13 [10], the export of bacterial toxins [45]. An alterative À14 [10] and human Charcot-Leyden crystal pro- refers to the possible accumulation of the molecule tein [21]. The next class of galectins is called the chi- to high levels of concentration at the plasma mem- mera type galectins and possess a combined brane, which is followed by their secretion in vesi- structure composed of a C-terminal CRD linked cles [28]. Galectins are, therefore, placed under to a proline, glycine and tyrosine rich N-terminal regulatory controls at the level of gene expression domain that is important for the formation of and secretion and their actions are modulated by higher order oligomers [22]. Galectin-3 is the only the regulation of the synthesis and modifications member of this family that has been described in of their glycan ligands by glycosyltransferases, the mammals and chicken, on activated macrophages, presentation of their ligands by specific glycoprotein basophils, mast cells and some epithelial and tumor counterreceptors and intracellular pathways of sig- cells [23]. The tandem repeat galectins constitute naling that are initiated by their binding to counter- the last class of galectins and have two distinct receptors [46]. CRDs. Galectins-4 [24], À6 [25], À8 [26], À9 [27] and À12 [10] fall in this category. 2. Molecular basis of cancer development due to galectins 1.2. Cellular functions of galectins The rationale for the development of molecules Several roles have been assigned to galectins that that share sequence homology yet perform opposite range from cell adhesion [28], regulation of cell functions can be cryptic but is nevertheless a com- growth [29,30], embryonic development [31] and mon phenomenon in biological systems. The eluci- immune processes like inflammation [32]. Even dation of the functioning of Bcl-2 family of
  3. 3. S.S. Hasan et al. / Cancer Letters 253 (2007) 25–33 27 apoptosis regulators provides a case in point. Cell sion of galectin-3 in normal thyroid follicular cells death is inhibited by Bcl-2 and Bcl-XL and is pro- by transfecting them with galectin-3 cDNA has moted by Bax, Bad and Bak. On parallel lines, been shown to lead to the development of a malig- galectin-1 [35,36,47] causes apoptosis in T cells nant phenotype [62] in the cells, which is associated while galectin-3 [37] prevents it. Galectin-3 has sig- with the increased expression of Rb, PCNA and nificant sequence homology with Bcl-2 [48] and they RCF [62], all known modulators of the G1 to S can be coimmunoprecipitated from Jurkat T cells transition and cellular proliferation. [37]. Galectin-3 has been shown to inhibit apoptosis Galectin-1 has also been shown to play an impor- induced by Fas, staurosporine and other agents [37] tant role in metastasis. It induces proliferation or by preserving the integrity of mitochondria and pre- apoptosis if its localization is extracellular and venting cytochrome c release in breast cancer cells, arrests growth if it is intracellular, thereby displaying besides not allowing reactive oxygen species to form the hallmark of location dependent function of [49]. The myriad critical functions of galectins make galectins [11]. Increased malignant potential of them potent tumorigenic molecules. While there is human thyroid tumors [63], glioma [64] and prostate no paucity of data [50], no recognizable trends adenocarcinoma [65,66] has been correlated with emerge from the studies of expression alterations. enhanced expression of galectin-1. Cyclophospha- The conflicting information in defining the roles of mides administered in low doses have been shown galectins is probably a result of differences in meth- to modulate levels of galectin-1 and Bcl-2 [67]. odologies and the chosen models. In this respect, Galectin-1 may increase adhesion of cancer cells to galectin-3 is one of the best understood of all the ECM. It may also promote apoptosis in T cells, members of its family [50]. Its expression in tumors thereby protecting the tumor from immune is associated with poor prognosis because the mole- responses. In cultures of human neoplastic astro- cule protects the cancerous cells from undergoing cytes, galectin-1 addition is found to increase cell death [11]. It could be used as a prognostic marker motility that is associated with reorganization of for thyroid cancer, colon cancer and cancers of head the actin cytoskeleton [11]. It also raised the levels and neck squamous cells, pancreas, bladder, stom- of RhoA, a protein that regulates the polymerization ach and kidneys [51]. In addition to galectin-3, and depolymerization of actin [64]. Moreover, glio- galectin-1 is also involved in cancer development blastoma cell migration is also increased by this as it anchors the molecule Ras, which is involved galectin. in cellular transformation [52]. While an established correlation between galec- Galectin-3 endows metastatic potential upon tin-1 mRNA expression and immunoreactive pro- tumor cells. Its expression in breast carcinoma cell tein [68] exists, there is a dearth of clear line leads to rapid spread of the cells [53,54]. The understanding of the molecular cascades involved use of galectin-3 antisense cDNA in a malignant in galectin-1 mediated development of metastasis. breast cancer cell line restores the characteristic fea- Most probably, it is the modulation of adhesion tures of normal cells, including contact inhibition, of cancer cells by galectin-1 that is partly responsi- serum dependence, and anchorage dependence ble for metastasis, as the molecule is known to both [11]. Normal astrocytes, oligodendrocytes and their stimulate and inhibit cellular adhesion by cross-link- precursor cell lines and glial progenitor cells do not ing oligosaccharides on integrins or by binding to express this protein but glioma cell lines show its laminin and sterically blocking its accessibility to presence [11]. Its function also depends on the site integrins [69]. of its localization as has been demonstrated in pros- Much attention has been focused upon galectin- tate cancer studies in which cytosolic accumulation 1 and -3 but similar advances lack in elucidation of of galectin-3 promoted metastasis, angiogenesis molecular aspects of functioning of other galectins. and abolition of anchorage dependence while its Some studies have been carried out with the result nuclear localization inhibited metastasis, anchorage that galectin-7 is now suggested to be an early tran- independence and promoted apoptosis [55–60]. Its scriptional target for the p53 product [70] and interaction with the highly conserved TTF-1, which galectin-8 has been recognized as the most abun- possesses differentiation and proliferation potential dant galectin found in tumor cells of different ori- and is thus implicated in thyroid cancer, indicates gins [71], besides being identified as closely related that galectin-3 may regulate transcription in several to PCTA-1, a surface marker of prostate cancer cell types [38,61]. Moreover, the increased expres- [72]. In other studies, galectin-9 and its allelic
  4. 4. 28 S.S. Hasan et al. / Cancer Letters 253 (2007) 25–33 variant ecalectin were found to be expressed in 17 4. Detection and identification of galectins of 21 tested human colorectal cancer lines [73]. Sub- sequently, a frame shift mutation was identified in The detection and identification of galectins has the coding sequence of the LGALS3 gene [73]. come a long way from the time when their ability The very fact that they are possibly redundant in to bind b-galactosides and their cross-reaction with function makes the study of other galectins indis- other galectins were exploited [83]. Haemagglutina- pensable. The failure of single and double knockout tion of trypsin treated erythrocytes was also widely mice to show significant phenotypic aberrations is used as an indicator of their presence but suffered enough reason to direct efforts toward other galec- from the problem of haemolysis of the cells, even tins [74,75]. under isotonic conditions [84]. This drawback was overcome when glutaraldehyde was used to 3. Role of glycosylation in galectin functioning strengthen the cells before they were used for galec- tin detection [85]. Glycosylation is an event known to be of para- With advances in techniques of molecular biology, mount importance to cellular functioning and inter- the methods of detection of galectins were also revo- actions. Its aberrations have been found in all types lutionized. Immunoscreening of cDNA was an of cancers and several glycosyl epitopes function as advancement over these primitive methods and tumor associated antigens [76]. Yet, the information resulted in the discovery of galectin-5 and -8 available about its role in carcinogenesis is quite [14,26]. Screening the tumor cDNA libraries from nebulous, primarily because of the lack of attention sera of afflicted patients identified another molecule, given to this field of investigation in comparison galectin-9 [27]. RT-PCR was another technique that with more attractive and rewarding avenues like was used to detect, with much success, the differential genetic studies. However, the implications of abnor- expression of galectins [86] and its results match well mal glycosylation in cancer development are being with Western blot data [87]. For all its popularity, the recognized. method still provides only an indirect estimate of The specific steps involved in the development of galectin levels. cancer because of incorrect glycosylation are not Recently, search algorithms have been developed known. One molecule that has been studied in to search for sequences that encode structures simi- much detail is GM3. It is found on the cell surface lar to the known galectin domains [8]. The screening [77]. Its interaction with CD9 and CD82 bestows of the GenBank databases identified seven new anti-metastatic potential on the cell [78]. GM3 putative galectins genes [8]. The fact that six of these and CD9 have even been found to be co-expressed sequences are expressed is a confirmation that they in several colorectal [79] and bladder cell lines [80]. are not pseudogenes [8]. Similar approaches have A reduction in the expression of this ganglioside been applied to other organisms with the result that may correlate with increased chances of metastasis there has been a massive increase in the number of [76]. possible galectins. Amongst a total of 20,000 genes While there is a shortage of unambiguous data, in C. elegans, 26 have been identified as candidate the possibility that there is a close analogy between galectin genes [8]. the expression patterns of glycoconjugates and their The ubiquitous distribution of galectins is evident binding galectins cannot be ruled out. GM3 has from the identification of candidate genes in the been found to be a ligand for galectin-8 [81]. This Mastadenovirus (U25120) [88], a lymphocystis galectin has two CRDs [26] and is involved in disease virus (L63545, 26549–27313 = 053R) [8], cross-linking of its ligands. Extracellularly, it can Drosophila (LP06039) [8], zebrafish (AI384777 and organize cell adhesion molecules on the same cell G47571) [8] and Arabidopsis (AC000348, T7N9.14) as well as on different cells and the matrix [82]. A [8], with the report in Arabidopsis being the first in change in the ligands of such a cellular anchor any plant [8]. may be very important, if not tantamount, to While all these methods are useful in the research metastasis. This could also be the missing link in laboratory, and have yielded 15 mammalian galec- the elucidation of galectin functioning and further tins till date [89], advances made in clinical studies studies to explore similar interactions between of galectins and their implication in tumorigenesis other galectins and their ligands should direct the has made the need to develop rapid and accurate course of research in the future. protocols for their accurate detection and estimation
  5. 5. S.S. Hasan et al. / Cancer Letters 253 (2007) 25–33 29 very pressing. Western blotting using anti-galectin does not vitiate the effects of others. The most logi- antibodies has been one of the biggest success stories cal approach under such circumstances would be as far as detection is concerned and has been used to the use of chemical inhibitors which is also a poten- confirm the increased expression of galectin-1 in tial means of treatment of cancer. pancreatic tumors [90,91]. Labeled antibodies have Modified citrus pectin is one compound that has also been used in situ to study expression patterns been tested to treat metastasis and it has been found of galectin-1 and -3 in lung cancer [92]. Membrane to inhibit galectin-3 [89]. A water-soluble derivative based methods have utilized the use of a LacNAc- of citrus pectin, which is a heterogeneous, high conjugated biotinylated-polyacrylamide probe to molecular weight branched polysaccharide, has demonstrate the increased expression of galectin-3 been shown to reduce tumor growth, metastasis in Escherichia coli [93]. The detection system was and angiogenesis in mice that were administered based on enzyme-streptavidin conjugates [93]. the inhibitor orally [89]. In vitro studies on human Quantification of galectins was not possible until umbilical vein endothelial cells also yielded similar the advent of ELISA, which provided information results [98]. Another modified derivative of citrus about the amounts of different galectins [89]. Com- pectin, GCS-100, induced apoptosis in myeloma mercially available detection and quantification sys- cells but direct involvement of galectin-3 has not tems can detect galectin-3 at as low a concentration been implicated [99]. as 0.2 ng mLÀ1 [94]. An alternative to sugar based inhibitors is artifi- With the emphasis on cancer-based research in cial peptide inhibitors [89]. These offer the advan- galectins, flow cytometry has been used to detect tage of ease of synthesis, along with equally potent total lectin, as well as galectin activity in cancer cells immune responses [100] that may facilitate the dis- [95]. This methodology is based on the use of Glyc- covery of naturally occurring molecules. Pentapep- PAA-fluo probes. The technique has proved tides based on the common Tyr-X-Tyr motif effectual for galectin-3 with the use of LacNAc found in glycomimetic peptides [101–106] have been and asialoGM-1 and the data match well with other used and found to be effective in millimolar ranges studies [89]. in preventing binding of several galectins [107]. The problem with most of the methods described The development of phage-display based analytical so far is their dependence on specific anti-galectin techniques has demonstrated that peptides as long antibodies. Recently, efforts have been made to as 15 residues are effective at nanomolar affinity devise strategies based on chemical approaches. for the anti-apoptotic galectin-3 [108]. They are also Photoaffinity based probes are being synthesized quite specific in their action and inhibit metastasis- [89]. In one case, benzophenone was attached on associated cell adhesion [89]. galactose-C3 and irradiated to link the galectin cap- A rather futuristic but nonetheless relevant tured by the sugar from a mixture of proteins and approach of dealing with galectin-induced cancer is the complex was visualized, in gel, by the use of gene therapy. It has been established that human fluorescent label attached to the other end of the galectin-3 is phosphorylated at serine 6 by casein probe. While this method annuls the need for anti- kinase [109,110] and this results in reduced binding bodies, it is still not proven for its efficacy as a diag- of laminin and asialomucin. Dephosphorylation nostic and prognostic tool. returns the sugar binding capacity to the galectin. Interestingly, mutations in serine 6 resulted in a 5. Research into therapeutic applications of galectins diminished ability of galectin-3 to protect cells from death induced by cis-platin [62], which is a common The ubiquitous distribution of galectins across anti-tumor agent. This finding should pave way for taxa is paralleled by an equally imposing level of the targeting of the galectin-3 gene in patients who redundancy in their functions [49]. This has ham- are found to suffer from galectin-3 induced cancers pered studies based on gene knockout models. and should be able to restore the potency of cis-platin. While galectin-1 and -3 knockouts have been shown The information provided by knockout studies is to possess defects, respectively, in olfactory axon relevant, but with the discovery of potent inhibitors, pathfinding [96] and neutrophil accumulation dur- the absence of successful models with disrupted ing inflammation [97], not much progress has been galectin genes and the rather nascent stage of devel- possible because of the pleiotropic nature of galec- opment of gene therapy in the present context, tins. The elimination of one from a model system research in galectins can progress only with the
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