Lectins - The target specific proteins. The next generation cancer target

THE NEXT GENERATION CANCER TARGET

LECTINSTHE TARGET SPECIFIC

PROTEINS

ByVigneshwaran V

OUTLINE OF CONTENTS

INTRODUCTION OF LECTINSCLASSIFICATION CARBOHYDRATE SPECIFICITY AND ITS BINDING MECHANISMTHE FUNCTIONAL ROLE OF LECTINS IN BIOLOGICAL SYSTEMS LECTINS AS THERAPEUTIC TOOLLECTINS IN CANCER RESEARCHANIMAL LECTINS IN CANCER PROGRESSION FUTURE PERSPECTIVES OF LECTIN IN CANCER THERAPYSUMMARY

LECTINSTHE TARGET SPECIFIC PROTEINS

The first lectin was found in the late nineteenth century in castor bean (Peter Hermann Stillmark 1888, 1889) and Boyd (1954) designated the name of “lectin” which originated from the Latin word “legere” carrying the meaning of “to select” .

Over the past several decades, lectins with different carbohydrate binding specificities and molecular structures were discovered in plants, microbes and animals.

Earlier – UNIVERSITY OF DORPAT, ESTONIA

BACKGROUND

THE BIRTH PLACE OF LECTINOLOGY


CHRONICLES OF LECTINSMore than 120 years ago, Peter Hermann Stillmark in his doctoral thesis presented in 1888 to the University of Dorpat, gave the earliest step in the study of proteins that have a very interesting feature: the ability to agglutinate erythrocytes.

This hemagglutinin was strongly used by Paul Ehrlich as model antigens for immunological studies. Thirty-one years after Stillmark, James B. Sumner, isolated from jack bean (Canavalia ensiformis) a protein that he called concanavalin A (ConA).

WHAT ARE LECTINS EXACTLY?

Thus, in 1995 Peumans and Van Damme proposed the most suitable definition for lectins. According to the “new” definition, “all plant proteins that possess at least one noncatalytic domain that binds reversibly to a specific mono- or oligosaccharide are considered as lectins”


HOW THE BEAN BECAMEA BULLETRICIN – THE FIRST LECTINIsolated from Ricinus communis (Castor seeds)

Beans of the castor tree (Ricinus communis) contain two closely related lectins, ricin and Ricinus communis agglutinin, RCA;21 the former is one of the deadliest poisons known: it is by weight about 10 times as toxic as cobra venom and, according to some estimates, a single molecule is sufficient to kill a cell.

It was used in warfare as a biological weapon and was targetted to kill many famous personalities.


The first lectin as a Chemical or biological warfare agentThe United States investigated ricin for its military potential during World War I. At that time it was being considered for use either as a toxic dust or as a coating for bullets and shrapnel.

During World War II the United States and Canada undertook studying ricin in cluster bombs.[

The Soviet Union also possessed weaponized ricin.

Under both the 1972 Biological Weapons Convention and the 1997 Chemical Weapons Convention, ricin is listed as a schedule 1 controlled substance.

A metal vial containing ricin from the 2003 ricin letters

Gupta R (2009). Handbook of Toxicology of Chemical Warfare Agents. Boston: Academic Press. ISBN 978-0-12-374484-5

https://en.wikipedia.org/wiki/Ricin


A dose of purified ricin powder the size of a few grains of table salt (1.7 mg)

can kill an adult human

Georgi Ivanov Markov, Bulgarian dissident writer was assassinated on a London street via a micro-engineered pellet containing ricin, fired into his leg 1978.

https://en.wikipedia.org/wiki/Ricin

LECTIN TRIGGERED PANIC SIGNALLING

The bus stop (right) where a prize-winning Bulgarian author and BBC broadcaster Georgi Markov was murdered by a Ricin


But castor oil from Ricinus communis is an excellent pharmaceutical agent

• Castor oil has various health benefits. The United States Food and Drug Administration (FDA) has categorized castor oil as "generally recognized as safe and effective " (GRASE) for over-the-counter use as a laxative with its major site of action the small intestine where it is digested into ricinoleic acid.

what about RICIN in it?

• Heating during the oil extraction process denatures and inactivates the protein, ricin, a toxic Lectin present in castor seed.


CLASSIFICATION OF LECTINS PLANT LECTIN CLASSIFICATION

LECTIN CLASSIFICATION BASED ON MOLECULAR STRUCTURE BASED ON CARBOHYDRATE BINDING DOMAIN

BASED ON CARBOHYDRATE SPECIFICITIES


Lectin proteins contain at least one carbohydrate-binding domain. Based on this, three major types of lectins are distinguished, namely

1. Merolectins, [Single carbohydrate binding domain- Monovalent]

2. Hololectins [At least two domain/ bind structurally same sugar]

3. Chimerolectins and [one or more C-binding domains/ well defined enzymatic activity that is independent from c-binding domain]

4. Superlectins [binds strucuturally unrelated sugars]

Classification - based on carbohydrate binding domain (Peumans and Van Damme Classification)

PLANT LECTIN CLASSIFICATION


CLASSIFICATION BASED ON GLYCAN SPECIFICITY OF LECTINS

A. MONOSACCHARIDES According to the monosaccharide for which they exhibit the highest affinity: mannose,galactose/N-acetylgalactosamine, N-acetylglucosamine (Glucose polymer),fucose, and N-acetylneuraminic acid (sugars are of the D configuration except for fucose which is L)

B. POLYSACCHARIDES (OLIGOSACCHARIDES ONLY)


Monosaccharide specific lectins – HIGH SPECIFICITY, BUT MODERATE AFFINITY

The affinity of the lectins for monosaccharides is usually weak, with association constants in the millimolar range, yet it is often highly selective. In particular, lectins specific for galactose do not react with glucose (its 4 epimer) or mannose (the 2 epimer of glucose), nor do those specific for mannose bindgalactose.

Similarly, with the exception of wheat germ agglutinin, members of the Nacetylglucosamine specificity group do not combine with N-acetylgalactosamine (and vice versa).

Relevant for the biological activities of lectins is the fact that of the numerous monosaccharides found in nature, only those listed above are typical constituents of surfaces of eukaryotic cells. Only in exceptional cases does one find lectins thatexhibit affinity for other sugars.

INTERESTINGLY LECTINS HAVE SPECIFICITIES THAT ARE THE TYPICAL CONSTITUENTS OF EUKARYOTIC CELL SURFACES!


MONOSACCHARIDES STRUCTURES

D-Glucose

C-2 EPIMER OF GLUCOSE C-4 EPIMER OF GLUCOSE


EUKARYOTIC CELL SURFACE GLYCOCONJUGATES


MONOSACCHARIDE SPECIFIC LECTINS


CERTAIN LECTINS INTERACT ONLY WITH OLIGOSACCHARIDES

The fact is that lectins often exhibit an exquisite specificity for di-, tri-, and tetrasaccharides (with association constants up to 1000-fold higher as compared with the monosaccharide) Moreover, lectins of the same specificity group may differ markedly in their affinities for different oligosaccharides.

The affinities of lectins to oligosaccharides may be influenced by the shape of the latter compoundswhich are flexible molecules with considerable freedom of rotation around the glycosidic bondsconnecting the individual monosaccharide constituents.


MOLECULAR STRUCTURE BASED CLASSIFICATION OF LECTINSAmino acid sequences and three dimensional structure of lectins makes its possible to Replace the traditional methods. Most lectins fall clearly into one of the following three classes:

(a) simple, Legumes CerealAmaryllidaceae and related familiesMoraceaeEuphorbiaceaeGalectins Pentraxins

(b) mosaic (or multidomain), and Viral heamagglutininsC-type lectinsP-type lectins I-type lectins

(c) macromolecular assemblies, although borderline cases exist.


LEGUME LECTINS - The largest and most thoroughly studied family of lectins

Concanavalin A from Jack bean, the prototype member of this family, was first isolated in 1919 by James Sumner (of urease fame) and shown by him, in 1936, to be specific for mannose and glucose.

Other well-studied legume lectins are phytohemagglutinin (PHA) from the red kidney bean, SBA, PNA, and ECorL.

They also contain a tightly bound Ca2+ and a transition metal ion, predominantly Mn2+, per subunit which are required for carbohydrate binding

The subunits of the legume lectins are commonly made up of single polypeptide chains of about 250 amino acids that may carry one or two N-linked oligosaccharides. In some lectins (e.g., those from pea and lentil) the polypeptides are fragmented into a light (R) and heavy (â) chain.


The canonical dimer, represented by concanavalin A.

The two spheres close to the bound sugar depict the bound metal ions (Ca2+ and Mn2+) present in all legume lectins.

Large changes have been observed in the crystallographic structure of concanavalin A upon demetalization of the lectin, which results in loss of its carbohydrate binding ability

Demetalization of legume lectins results in loss of its carbohydrate binding activity


How exactly does the lectins bind to carbohydrates

The combining sites of lectins are in the form of shallow depressions on the surface of the protein.

Typically, only one or two edges or faces of the carbohydrate ligand are bound to the protein. This is in contrast to carbohydrate-binding bacterial periplasmic receptors, specific for, e.g., glucose or galactose, in which the ligand is buried in the interior ofthe protein.

In lectins, the combining sites appear to be preformed, since few conformational changesoccur upon ligand binding.

“the sites within a lectin family are similar, but quite different in different families, even if the specificity is the same, emphasizing the fact that nature finds different solutions to the problem of the design of combining sites for structurally similar ligands.”


INTERACTIONS INVOLVED IN LECTIN CARBOHYDRATE BINDING

Lectins combine with carbohydrates by a networkHydrogen bondsHydrophobic interactions;Coordination with metal ions may also play a role.

The hydrogen bonds are formed between carbohydrate hydroxyl groups andNH groups, hydroxyls, and oxygen atoms of the protein.

When each of two adjacent hydroxyls of a monosaccharide interacts with a different atom of the same amino acid (e.g., the two oxygens of the carboxylate of glutamic or aspartic acid), they form bidentate hydrogen bonds. Such bonds are quitecommon in protein-carbohydrate complexes.


CARBOHYDRATE BINDING AMINO ACIDS IN VARIOUS LECTINS


THE FUNCTIONAL ROLE OF LECTINS INBIOLOGICAL SYSTEMS

IN VIRUS• In viruses, lectins (haemagglutinins) play an important role in the process of fusion and

attachment with the host cells. • The haemagglutinin (HA) of influenza virus is derived from the biosynthetic precursor HAO

(biosynthetic precursor of influenza virus haemagglutinin) and controls cell recognition and attachment

IN FUNGI • Lectins in fungi are believed to be involved in metabolic activities, growth, dormancy, self-

defense, morphogenesis, symbiosis and parasitic infections, which, however, are still full of uncertainties and await corroboration




MICROBIAL LECTINS –HEAMAGGLUTININS, ADHESINS AND TOXINS

Many microorganisms exploit host cell surface glycans (LECTINS) as receptors for cell attachment and tissue colonization, and a large number of pathogenic species depend on these interactions for infection.

The first microbial hemagglutinin identified was in the influenza virus, and it was shown by Alfred Gottschalk in the early 1950s to bind to erythrocytes and other cells though sialic acid residues of cell surface glycoconjugates.

Nathan Sharon and colleagues first described bacterial surface lectins in the 1970s. These lectins also have hemagglutinating activity, but their primary function is to facilitate attachment or adherence of bacteria to host cells, a prerequisite for bacterial colonization and infection.

Thus, bacterial lectins are often called adhesins, and the glycan ligands on the surface of the host cells are called receptors.


BACTERIAL LECTINS Bacterial lectins occur commonly in the form of elongated, submicroscopic, multisubunit protein appendages, known as fimbriae (hairs) or pili (threads), which interact with glycoprotein and glycolipid receptors on host cells.

Many adhesins contain carbohydrate recognition domains (CRDs) that bind to the same carbohydrates as endogenous mammalian lectins

Detailed studies of the specificity of microbial lectins have led to the identification and synthesis of powerful inhibitors of adhesion that may form the basis for therapeutic agents for treating infection


Bacterial lectins – Macromolecular assemblies (Refer classification on Molecular structure)




THE VITAL ROLE OF LECTINS IN PLANTS Plant lectins play vital self-defending roles by deleteriously affecting the growth of

insects or hindering oviposition behavior. The vulnerable plant organs like seeds usually possess an abundance of lectins .

Expression of lectins in plants is sensitive to stress factors and environmental variations, like insect herbivory, drought, wounding, salt stress, hormone treatment and pathogen invasion .

Tobacco leaves normally express a very low level of lectin, however, when treated with jasmonates or threatened by insect herbivory, lectin expression was found to be upregulated .

Plant lectins may also be involved in the interactions between plant and soil bacteria to establish a symbiotic relationship. For example, legume lectins contribute to the binding of rhizobia to the roots and formation of nodules


LECTINS IN CANCER RESEARCH


CARBOHYDRTATES AND THE NEOPLASTIC PROCESS

The malignant tumors, or cancers, account for approximately 7.8 million deaths peryear, thus becoming the second greatest cause of death worldwide, only behind thecardiovascular disease

Carbohydrates are biomolecules that have enormous potential for encoding biological information. These combined-molecules (Glycoproteins and Glycolipids) are responsible for different biological interactions between the cell and the extracellular environment

Regarding the neoplastic cells, the glycosylation of these proteins and lipids is changed,which generates membrane signaling molecules capable of inducing several processes directly related to tumor progression such as cell adhesion, angiogenesis, cellular mitosis and metastasis.

Certain changes in glycans occur frequently in neoplastic cells and may be considered"tumor-specific", establishing a correlation between the stage of disease progression and prognosis of the same


ALTERED GLYCANS – THE KEY TO IDENTIFY TRANSFORMED CELLS

Certain changes in glycans occur frequently in neoplastic cells and may be considered "tumor-specific", establishing a correlation between the stage of disease progression and prognosis of the same

Several common alterations in oligosaccharide structures, such as

an increase in 1,6-branching of N-linked chainsfucosylated N-linked glycan (in HCV and Hepatocellular Carcinoma) changes in sialylation Mucins (rich in serine and threonine)Lewis sugarsGalectins, have been described various pathologies like epithelial tumors, including those of the breast, colon, and prostate etc.

Therefore, monitoring of changes in glycosylation or glycan structures in cancer development could provide profitable references to researchers and clinicians. By far, the majority of cancer biomarkers approved by FDA(American Food and Drug Administration) are glycoproteins or glycosylated


Why lectins are extraordinary tool for cancer research?

Tumor Cell Membrane Glycosylation and Lectins – the key of selectivity

• Tumor cells display aberrant patterns of glycosylation in cell surface .

• Alteration on membrance glycosylation known to be progressive markers.

• Carbohydrates expressed in tumor cells are either adhesion molecules or modulate adhesion receptor function.

[among them are, increase in N-glycan and sialic acid content in cell surface]


Preferential binding of lectins to transformed cells

• Changes in glycosylation involves interaction of endogenous and exogenous lectins , that can alter the response of cancer cells. [Con A, WGA]

• The lectins main significance lies in their properties in cell recognition.

• Lectins are also used to detect malignant changes in transformed cells due to the changes in cell surface glycans.


GARLIC LECTIN – A TRUE DIETARY ANTICANCER DRUG Garlic is one of the natural food and is hierarchically ranked at the top of foods possessing a cancer-preventive property by the National Cancer Institute’s Experimental Food Program

Garlic lectin purified from garlic bulbs on the production of cytokines such as interleukin-12 (IL-12) and interferon- (IFN-) in the mouse.

IL-12 is thought to induce a cytokine cascade with antiangiogenic effects mediated by IFN- and has been shown to induce strong direct antitumor immunity by activating NK and CD8+ T cells, with CD8+-dependent tumor regression and rejection

A research group from Japan isolated a lectin from garlic bulbs and demonstrated that this garlic lectin was toxic towards human histiocytic lymphoma cells and human promyelocytic leukemia cells by inducing apoptosis, but not toxic to normal human leukocytes, providing an evidence for the previous case-control studies


Con A – the potential anticancer Lectin Concanavalin A was the first reported legume lectin and had been demonstrated to bear apoptosis-inducing and autophagic-inducing activities. The utilization of Con A as an anti-cancer agent has reached pre-clinical trials. Concanavalin A (ConA) is a Ca2+/Mn2+-dependent and mannose/ glucose-binding legume lectin, which first isolated from the jack bean in 1916


Con A induces cancer cell death targeting autophagy, apoptosis, and angiogenesis


ANTITUMOR POTENTIAL OF KOREAN AND EUROPEAN MISTLETOE LECTINS

Antitumor lectins are also found in traditional Chinese medicines, like mistletoe. Mistletoe is one of the herbs which have been successfully used in the treatment of human cancers, with a history of more than 80 years’ anti-cancer study and over 25 years’ clinical trials in Europe.

Mistletoe has been reported to stimulate immune system by increasing the number and activity of white blood cells and enhancing a variety of cytokines

The effective components of mistletoe are viscotoxins and lectins. There are three types of lectins in mistletoe, lectin I(ML-I), lectin II(ML-II) andlectin III(ML-III).Ml-I contains a lectin chain (B chain) and an enzyme chain (A chain)

Effective on Pancreatic cancers, Jurkat leukemic T cells, Human hepatoma etc.


Dietary MISTLETOE lectin supplementation and its impact on tumor growthThe growth of a murine non-Hodgkin lymphoma (NHL) tumour has been shown to be reduced by incorporating mistletoe lectin (ML-1) into the diet. Based on observations from animal model system, and published data, the following sequence of events is suggested following the oral intake of mistletoe lectins:

1. MLs bind to Peyer´s patch M cells through galactose/N-acetyl glucosamine receptors. 2. Stimulation of cytokine production and their release : increased plasma levels. 3. Activation and release of splenic lymphocytes and macrophages, activation of NK. 4. Tumour infiltration by lymphocytes, NK and macrophages. 5. Production and release of antiangiogenic factors : reduced tumour vascularisation6. Reduced availability of nutrients for tumour growth and decreased oxygen supplies. 7. Cytotoxic effects on tumour cells. 8. Induction of apoptosis. 9. Tumour cell death

I.F. Pryme, S. Bardocz, A. Pusztai and S.W.B. Ewen, Dietary mistletoe lectin supplementation and reduced growth of a murine non-Hodgkin lymphoma, Histol Histopathol (2002) 17: 261-271


EUROPEAN MISTLETOE (Viscum album)


CEREAL LECTIN- WHEAT GERM AGGLUTININ (WGA) – IMMUNOMODULATORY AND ANTIPROLIFERATIVE ACTIVITY

NOTE: IMAGE SHOWS THE SOURCE OF LECTIN

wheat germ agglutinin can induce the secretion of cytokines such as interleukin-12 (IL-12), tumor necrosis factor (TNF)-, and interferon- (IFN-) in murine peritoneal macrophages.Exhibited antiprolifeartive activity on pancreatic cancer cells.


SOY BEAN AGGLUTININ (SBA) – A CYTOTOXIC AND ANTIPROLIFERATIVE LECTIN FROM SOY BEAN


SOY BEAN LECTIN (SBA) has a potential to inhibit hepatoma and mammary cell carcinoma

SBA is galactose and N-acetyl-galactosamine specific lectin


Galanthus nivalis agglutinin (GNA)

Snowdrops contain also an active lectin or agglutinin named GNA for Galanthus nivalis agglutinin.

Galanthus nivalis agglutinin (GNA)-related lectin family, a superfamily of strictly mannose-binding specific lectins widespread among monocotyledonous plants, is well-known to possess a broad range of biological functions such as anti-tumor, anti-viral and anti-fungal activities.

PEANUT AGGLUTININ (PNA)

• The antitumorigenic effects of Peanut agglutinin (PNA) isolated from Arachis hypogea in Dalton's lymphoma (DL) bearing mice

• In vitro data showed that PNA at 0.1-100 μg/ml dose exhibit selective antiproliferative activity on various cancer cell lines without displaying cytotoxic effect on normal cells

• PNA was found to induce autophagic and apoptotic cell death in HeLa cells

Food Chem Toxicol. 2014 Feb;64:369-77.

In vitro and in vivo antitumor effects of Peanut agglutinin through induction of apoptotic and autophagic cell death.



ANIMAL LECTINS ROLE IN TUMOR PROGRESSION


PICTURE SOURCE: http://news.nationalgeographic.com/2015/09/150910-human-evolution-change/

ANIMAL LECTINSAccording to the historical overview of animal lectins by David C. Kilpatrick, as early as 19th century, a lectin of animal origin, which is presently known as galectin-10, hasbeen found in pathological tissues and sputum samples of asthmatics in a crystal-like form.

However, at that time its carbohydrate-binding properties had not been identifiedand the concept of lectin had not yet been proposed. It was not until 1970s that Stockert et al. for the first time introduced an agglutinin from the rabbit liver as a mammalianlectin

Mammalian lectins include, Collectins (Mannan binding lectins), C-type lectins (Selectins), Galectins, Annexins etc. (lectins and lectin-like proteins are involvedin many important processes like cell-cell adhesion, cell migration,cell recognition, anti-inflammation and vesicle trafficking)

IN ANIMALS THE LECTINS TAKE EVEN MORE DIVERSE ROLES!!


GALECTINS • Galectins constitute a family of animal lectins that bind bgalactoside residues through their carbohydrate

recognition domains (CRD). Galectins are composed of a group of glycan-binding proteins which share common structures and a carbohydrate recognition domain, but differ in carbohydrate specificityand by far there are 15 family members

According to their structure, galectins are classified into three groups:

I) ‘‘proto-type’’ galectins, containing a single CRD including galectin (Gal) -1, -2, -7, -10, -13, and -14,

II) chimera-type galectins which contain a single CRD and a large amino-terminal non-lectin domain with Gal-3 being its only representative, and

III) tandem-repeat type galectins which have two CRD linked by a peptide sequence of variable length and include Gal-4, -8, -9, and -12 [11]. Galectins are expressed in a wide variety of cells and tissues and play an important role in cellular mechanisms including cell signaling, proliferation, migration, apoptosis, and mRNA splicing .

Galectins are also associated with different pathologies such as allergies, autoimmune diseases, atherosclerosis, infectious processes, and cancer


GALECTINS – A SIGNAL LINKED TO MALIGNANCY

Most of the Galectins - lectins are up-regulated in several types of tumors and this feature correlates with tumor progression, aggressiveness and acquisition of a metastatic phenotype.

• Two important members of the galectin family, galectin-1 and gal-3, are found closely connected with human cancers. Gal-1 is expressed in both malignant cells and normal cell lines at different levels and distribution while gal-3 is only detectable in cancer cells

• Mutations of Ras genes represent around 20 % of all human tumor cases and for pancreatic cancer the figure even goes up to 90 %. Gal-1 has been documented to be a vital partner of Ras.


PLATELETS AS TARGETS FOR TUMORAL ANGIOGENESIS

Emerging evidence implicates a key role for platelets in site specific neovascularization at ischemic tissues and the tumor microenvironment as they are major storage and delivery vehicles for pro- and antiangiogenic growth factors including,

o Vascular endothelial growth factor (VEGF), o endostatin, and o thrombospondin-1 (TSP-1), o and cytokines and chemokines, such as stromal derived factor 1 a (SDF-1a)

and IL-8 among others.

These proteins are stored together with coagulation factors in platelet alpha-granules, which upon activation can degranulate and influence the local angiogenic response.


TUMOR EXPRESSED GALECTINS TRIGGER PLATELET MEDIATED ANGIOGENESIS

• Both soluble and immobilized Gal-1 and Gal-8 bind and activate platelets, promoting adhesion, aggregation and granule secretion

• A growing body of experimental evidence suggest that galectins, mainly Gal-1, -3 and -8, are directly involved in angiogenesis as they induce endothelial cell proliferation, chemotaxis, in vitro capillary tube formation, and in vivo neovascularization. Particularly, the Gal-1-N-glycan axis can link tumor hypoxia to vascularization and promotes VEGF-like signals in tumors that are refractory to anti-VEGF therapy

Galectins – induces VEGF like signals


Platelets stimulated by galectins trigger endothelial cell proliferation and capillary-like tube formation. Tube formation in Matrigel-coatedwells was analyzed under an inverted light microscope.

Human microvascular endothelial cells 1 (HMEC-1) from the Center of Disease Control and Prevention (CDC, Atlanta, USA). Cells grown in RPMI supplemented with fetal bovine serum (10%)


Gal-3 in drug resistance, evading Apotosis

Gal-3 has been demonstrated to increase the survival rate of tumor cells under different apoptotic stimulations.

Gal-3 has a sequence highly similar with the BH1 domain of the Bcl-2 family and also contains the Asp-Trp-Gly-Arg (NWGR) motif in the C-terminal domain which was taken as the anti-death motif and the active compartment for Bcl-2’s anti-apoptotic activity

• BT549 cells expressing no gal-3 underwent apoptosis after treatment with CDDP ((cisdiamminedichloroplatnum). While sense-transfected BT549 cells expressing gal-3 survived from CDDP-induced apoptosis, confirming the apoptosis-resistance role of gal-3.


Gal-3 evades AnoikisThe interaction between cells and the matrix regulate many important biological

processes, like gene expression cell differentiation and cell growth. When cells are detached from the extracellular matrix, important signal conduction will be disrupted, culminating in a type of programmed cell death, termed anoikis.

Intergrins regulate cellular adhesion to ECM, and in turn adhesion to ECM controls the transition of cell cycle Because cyclin D1 and cyclin E-associated kinases play important roles in G1-S transition and activations of cyclin D and cyclin requires cell adhesion. For normal cells, once detached from the extracellular matrix (ECM),they fail to transit the cell cycle and undergo anoikis.

Gal-3 expressed in tumor cells could help malignant cells survive in a disseminated condition by regulating cell cycle arrest at an anoikis-insensitive point (late G1)

ADHESION – AN ATTACHMENT TO APOPTOSIS!


Galectins in tumor Immunity escape and angiogenesis

Gal-1 has been documented to be a negative regulator of T cells. In immune-potent mice, there were more CD4+ and CD8+ undergoing apoptosis when tumor cells expressed higher levels of gal-1.

Gal-1 may contribute to immunosuppression in tumor immune escape.

Gal-1 and Gal-3 are two hypoxia-regulated proteins, could also serve as mitogens and promote the proliferation of endothelial cells. Gal-3 extracellularly interacts with LGAFLS3BP (lectin galactoside binding soluble 3 binding protein) and activate FAK-mediated (Focal adhesion kinase) signaling pathways, initiating an angiogenic cascade.


SELECTINS [C-TYPE LECTINS] – IN TUMOR PROGRESSION

Selectins are a family of three transmembrane proteins of the C-type lectin family which include L-selectin, P-selectin and E-selectin.

These selectins recognise sialyl Lewis X (SLeX) and sialyl Lewis A (SLeA) sialic acid containing ligands which are predominantly present at the tips of O-linked glycans on the surface of leukocytes.

Tumor derived mucins, from carcinomas such as breast, colon, pancreas and stomach, frequently show increased level of Lewis glycans, and hence the interaction between tumor cells and the vasculature were thought and subsequently shown to be mediated by selectins on the endothelial cells


Mammalian letins as a cancer therapeutic target

• Due to the importance of mammalian lectins in cancer development, the idea of taking carcinoma-related lectins as therapeutic targets has been proposed. Trials have been conducted to block cancer development by targeting against important lectins (Like Gal1, Gal3 etc)

• Research showed that the invasive ability of lymphoma could be greatly reduced by blocking the expression of gal-7.

• Metastasis of colorectal carcinoma to the liver could be greatly reduced by D galactose ( infusions) targeting against liver lectins.


FACTS ABOUT OTHER LECTINS


SNAKE VENOMS ALSO HOLDS A PROMISING SOURCE OF CYTOTOXIC LECTINS


Lectins are a growing class of HIV-1 inhibitors under consideration as microbicide candidates.

Lectins inhibit HIV-1 entry by binding to carbohydrate structures found on the viral envelope.

Examples of anti-HIV lectins include Cyanovirin- N (CV-N), Griffithsin (GRFT) and Snowdrop lectin (GNA).BanLec

The HIV-1 envelope protein gp120 contains 20–30 possible N-linked glycosylation sites. These carbohydrate structures make up50% of the molecular weight of the protein.Glycosylation affects aspects of the viral life cycle including protein folding, cellular transport, binding to cellular receptors, trans-infection by dendritic cells,and shielding from the immune response


A LECTIN FROM BANANA INHIBITS HIV REPLICATION

The lectin termed BanLec, isolated from the ripened fruit of the banana (Musa acuminata cultivars), exists as a dimer with a molecular mass of 30 kDa (21). It is a member of the jacalin related lectin family and can recognize high mannose structures. BanLec inhibits HIV-1 infection by binding to the glycosylated viral envelope and blocking cellular entry.

BanLec is a potential component for an anti-viral microbicide that could be used to prevent the sexual transmission of HIV-1.

One potential benefit of the use of lectins as anti-HIV agents is their ability to target multiple different glycosylation sites on the virus, thus making it more difficult for resistance to develop.


SUMMARYLECTINS HAS A POTENTIAL IN CANCER THERAPY

LECTINS FOR TARGETTING ALTERED GLYCANS

LECTINS FOR INHIBITING ANGIOGENESIS

LECTINS (ENDOGENOUS) AS A TARGET IN MALIGNANCY

LECTINS FOR INDUCING APOPTOSIS/ AUTOPHAGY

LECTINS AS AN IMMUNOMODULATOR IN ADJUVANT CANCER IMMUNOTHERAPY


THANK YOU

AUTHOR INFORMATION

By Vigneshwaran V.

PhD Scholar, Kuvempu University, INDIA

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Lectins - The target specific proteins. The next generation cancer target