This presentation encompasses the description and classification of plant and animal lectins, with special reference to its role in cancer progression.
2. OUTLINE OF CONTENTS
INTRODUCTION OF LECTINS
CLASSIFICATION
CARBOHYDRATE SPECIFICITY AND ITS BINDING MECHANISM
THE FUNCTIONAL ROLE OF LECTINS IN BIOLOGICAL SYSTEMS
LECTINS AS THERAPEUTIC TOOL
LECTINS IN CANCER RESEARCH
ANIMAL LECTINS IN CANCER PROGRESSION
FUTURE PERSPECTIVES OF LECTIN IN CANCER THERAPY
SUMMARY
LECTINS
THE TARGET SPECIFIC PROTEINS
3. 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
LECTINS
THE TARGET SPECIFIC PROTEINS
4. CHRONICLES OF LECTINS
More 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”
LECTINS
THE TARGET SPECIFIC PROTEINS
5. HOW THE BEAN BECAME
A BULLET
RICIN – THE FIRST LECTIN
Isolated 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
6. The first lectin as a Chemical or biological warfare agent
The 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
LECTINS
THE TARGET SPECIFIC PROTEINS
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.
7. LECTIN TRIGGERED PANIC SIGNALLING
The bus stop (right) where a prize-winning
Bulgarian author and BBC broadcaster
Georgi Markov was murdered by a Ricin
LECTINS
THE TARGET SPECIFIC PROTEINS
8. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
9. CLASSIFICATION OF LECTINS
PLANT LECTIN CLASSIFICATION
LECTIN CLASSIFICATION BASED ON MOLECULAR STRUCTURE
BASED ON CARBOHYDRATE BINDING DOMAIN
BASED ON CARBOHYDRATE SPECIFICITIES
LECTINS
THE TARGET SPECIFIC PROTEINS
10. 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
LECTINS
THE TARGET SPECIFIC PROTEINS
11. 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)
LECTINS
THE TARGET SPECIFIC PROTEINS
12. 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 bind
galactose.
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 that
exhibit affinity for other sugars.
INTERESTINGLY LECTINS HAVE SPECIFICITIES THAT ARE THE TYPICAL
CONSTITUENTS OF EUKARYOTIC CELL SURFACES!
LECTINS
THE TARGET SPECIFIC PROTEINS
16. 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 compounds
which are flexible molecules with considerable freedom of rotation around the glycosidic bonds
connecting the individual monosaccharide constituents.
LECTINS
THE TARGET SPECIFIC PROTEINS
17. MOLECULAR STRUCTURE BASED CLASSIFICATION OF
LECTINS
Amino 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
Cereal
Amaryllidaceae and related families
Moraceae
Euphorbiaceae
Galectins
Pentraxins
(b) mosaic (or multidomain), and
Viral heamagglutinins
C-type lectins
P-type lectins
I-type lectins
(c) macromolecular assemblies, although borderline cases exist.
LECTINS
THE TARGET SPECIFIC PROTEINS
18. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
19. 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
LECTINS
THE TARGET SPECIFIC PROTEINS
20. 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 changes
occur 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.”
LECTINS
THE TARGET SPECIFIC PROTEINS
21. INTERACTIONS INVOLVED IN LECTIN CARBOHYDRATE BINDING
Lectins combine with carbohydrates by a network
Hydrogen bonds
Hydrophobic 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 quite
common in protein-carbohydrate complexes.
LECTINS
THE TARGET SPECIFIC PROTEINS
23. THE FUNCTIONAL ROLE OF LECTINS IN
BIOLOGICAL 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
LECTINS
THE TARGET SPECIFIC PROTEINS
26. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
27. 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
LECTINS
THE TARGET SPECIFIC PROTEINS
28. Bacterial lectins – Macromolecular assemblies
(Refer classification on Molecular structure)
LECTINS
THE TARGET SPECIFIC PROTEINS
31. 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
THE TARGET SPECIFIC PROTEINS
33. CARBOHYDRTATES AND THE NEOPLASTIC PROCESS
The malignant tumors, or cancers, account for approximately 7.8 million deaths per
year, thus becoming the second greatest cause of death worldwide, only behind the
cardiovascular 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
LECTINS
THE TARGET SPECIFIC PROTEINS
34. 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 chains
fucosylated N-linked glycan (in HCV and Hepatocellular Carcinoma)
changes in sialylation
Mucins (rich in serine and threonine)
Lewis sugars
Galectins, 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
LECTINS
THE TARGET SPECIFIC PROTEINS
35. 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]
LECTINS
THE TARGET SPECIFIC PROTEINS
36. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
37. 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
LECTINS
THE TARGET SPECIFIC PROTEINS
38. 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
LECTINS
THE TARGET SPECIFIC PROTEINS
39. Con A induces cancer cell death targeting autophagy, apoptosis,
and angiogenesis
LECTINS
THE TARGET SPECIFIC PROTEINS
40. 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) and
lectin 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
41. Dietary MISTLETOE lectin supplementation and its
impact on tumor growth
The 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 vascularisation
6. 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
LECTINS
THE TARGET SPECIFIC PROTEINS
43. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
44. SOY BEAN AGGLUTININ (SBA) – A CYTOTOXIC AND
ANTIPROLIFERATIVE LECTIN FROM SOY BEAN
LECTINS
THE TARGET SPECIFIC PROTEINS
SOY BEAN LECTIN (SBA) has a potential to inhibit hepatoma
and mammary cell carcinoma
SBA is galactose and N-acetyl-galactosamine specific lectin
45. LECTINS
THE TARGET SPECIFIC PROTEINS
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.
46. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
48. ANIMAL LECTINS
ROLE IN TUMOR PROGRESSION
LECTINS
THE TARGET SPECIFIC PROTEINS
PICTURE SOURCE: http://news.nationalgeographic.com/2015/09/150910-human-evolution-change/
49. ANIMAL LECTINS
According 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, has
been 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 identified
and 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 mammalian
lectin
Mammalian lectins include, Collectins (Mannan binding lectins), C-type lectins
(Selectins), Galectins, Annexins etc. (lectins and lectin-like proteins are involved
in 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!!
LECTINS
THE TARGET SPECIFIC PROTEINS
50. 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
LECTINS
THE TARGET SPECIFIC PROTEINS
51. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
52. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
53. 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
LECTINS
THE TARGET SPECIFIC PROTEINS
54. Platelets stimulated by galectins trigger endothelial cell proliferation and
capillary-like tube formation. Tube formation in Matrigel-coated
wells 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%)
LECTINS
THE TARGET SPECIFIC PROTEINS
55. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
56. Gal-3 evades Anoikis
The 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!
LECTINS
THE TARGET SPECIFIC PROTEINS
57. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
58. 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
LECTINS
THE TARGET SPECIFIC PROTEINS
59. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
61. SNAKE VENOMS ALSO HOLDS A PROMISING SOURCE OF
CYTOTOXIC LECTINS
LECTINS
THE TARGET SPECIFIC PROTEINS
62. 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
LECTINS
THE TARGET SPECIFIC PROTEINS
63. 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.
LECTINS
THE TARGET SPECIFIC PROTEINS
64. SUMMARY
LECTINS 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
LECTINS
THE TARGET SPECIFIC PROTEINS
65. THANK YOU
AUTHOR INFORMATION
By Vigneshwaran V.
PhD Scholar, Kuvempu University, INDIA
Follow me at,
https://twitter.com/vvigneshwaran14
Mail to,
vikkku@yahoo.com
http://madonscience.blogspot.in/
MAD
ON SCIENCE
LECTINS
THE TARGET SPECIFIC
PROTEINS