Plant Lectins: Targeting Programmed Cell Death Pathways As Antitumor Agents

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Plant lectins: targeting programmed cell death pathways as antitumor agents. Int J Biochem Cell Biol

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The International Journal of Biochemistry & Cell Biology 43 (2011) 1442–1449

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Review

Plant lectins: Targeting programmed cell death pathways as antitumor agents

1 1 1 ∗ ∗

Lei-lei Fu , Cheng-cheng Zhou , Shun Yao , Jia-ying Yu, Bo Liu , Jin-ku Bao

School of Life Sciences & State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China

a r t i c l e i n f o a b s t r a c t

Article history: Lectins, a group of highly diverse, carbohydrate-binding proteins of non-immune origin that are ubiq-

Received 7 June 2011

uitously distributed in plants, animals and fungi, are well-characterized to have numerous links a wide

Received in revised form 11 July 2011

range of pathological processes, most notably cancer. In this review, we present a brief outline of the

Accepted 12 July 2011

representative plant lectins including Ricin-B family, proteins with legume lectin domains and GNA fam-

Available online 20 July 2011

ily that can induce cancer cell death via targeting programmed cell death pathways. Amongst these

above-mentioned lectins, we demonstrate that mistletoe lectins (MLs), Ricin, Concanavalin A (ConA) and

Keywords:

Polygonatum cyrtonema lectin (PCL) can lead to cancer cell programmed death via targeting apoptotic

Plant lectin

Cancer pathways. In addition, we show that ConA and PCL can also result in cancer cell programmed death by

targeting autophagic pathways. Moreover, we summarize the possible anti-cancer therapeutic implica-

Programmed cell death (PCD)

Apoptosis tions of plant lectins such as ConA, Phaseolus vulgaris lectin (PHA) and MLs that have been utilized at

Autophagy different stages of preclinical and clinical trials. Together, these ﬁndings can provide a comprehensive

perspective for further elucidating the roles of plant lectins that may target programmed cell death path-

ways in cancer pathogenesis and therapeutics. And, this research may, in turn, ultimately help cancer

Contents

1. Introduction ...... 1443

2. Molecular mechanisms of Ricin-B family-induced apoptosis ...... 1443

2.1. Mistletoe lectins ...... 1443

2.2. Other Ricin-B family lectins ...... 1444

3. Molecular mechanisms of proteins with legume lectin domains-induced apoptosis or autophagy ...... 1445

3.1. Concanavalin A ...... 1445

3.2. Other proteins with legume lectin domains ...... 1445

4. Molecular mechanisms of Galanthus nivalis agglutinin (GNA) family-induced apoptosis and/or autophagy ...... 1446

4.1. Polygonatum cyrtonema lectin ...... 1446

4.2. Other GNA-related lectins ...... 1447

5. Possible therapeutic implications of plant lectins in cancer ...... 1447

6. Concluding remarks and future directions ...... 1448

Acknowledgments ...... 1448

References ...... 1448

Abbreviations: ABA, garicus bisporus agglutinin; Apaf-1, apoptosis-associated factor-1; APC, adenomatous polyposis coli; APO-1, apoptosis antigen-1; CM-I, Chinese

mistletoe lectin-I; ConA, Concanavalin A; EEA, Euonymus europaeus agglutinin; ERK, extracellular signal-regulated kinase; FADD, Fas-associated protein with death domain;

GNA, Galanthus nivalis agglutinin; JNK, c-Jun N-terminal kinase; KML, Korean mistletoe lectin; LNL, Liparis noversa lectin; LysM, lysin motif; MAPK, mitogen-activated

protein kinase; MLs, mistletoe lectins; PCD, programmed cell death; MMP, mitochondrial membrane potential; NMR, nuclear magnetic resonance; OJL, Ophiopogon

japonicus lectin; PCL, Polygonatum cyrtonema lectin; PHA, Phaseolus vulgaris lectin; PI3K, phosphatidylinositol 3 kinase; POL, Polygonatum odoratum lectin; RBA, rice bran

agglutinin; RIPs II, type II ribosome-inactivating proteins; ROS, reactive oxygen species; SAPK, stress-activated protein kinase; SFL, Sophora ﬂavescens lectin; TNF-␣,

tumor necrosis factor-␣; TRAIL, TNF-related apoptosis inducing ligand; XIAP, X-linked inhibitor of apoptosis protein.

∗

Corresponding authors. Tel.: +86 28 85411914; fax: +86 28 85411914.

E-mail addresses: [email protected] (B. Liu), [email protected] (J.-k. Bao).

These authors contributed equally to this work.

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L.-l. Fu et al. / The International Journal of Biochemistry & Cell Biology 43 (2011) 1442–1449 1443

1. Introduction mistletoes, which has received much attention for their anti-

proliferative and apoptosis-inducing mechanisms in cancer cells

Lectins, a group of highly diverse non-immune origin pro- (Seifert et al., 2008) (Fig. 2A). So far, MLs have been divided into

teins ubiquitously distributed in plants, animals and fungi, contain three distinct types, namely, ML-I, ML-II and ML-III. They are het-

at least one non-catalytic domain which enables them to selec- erodimeric glycoproteins that consist of an A-chain comprising

tively recognize and reversibly bind to speciﬁc free sugars or three conserved individual domains and a B-chain containing two

glycans present on glycoproteins and glycolipids without alter- domains with the similar conﬁguration (Thies et al., 2005). In the

ing the structure of carbohydrate (Van Damme et al., 1998). Plant three types of MLs, sugar-binding speciﬁcity of B-chain may play

lectins are divided into 12 different families according to their an important role in determining selective cytotoxicity for cancer

different carbohydrate-binding speciﬁcities, such as (1) Agaricus cells via interacting with certain sugar-chains or sugar-containing

bisporus agglutinin homologs, (2) Amaranthins, (3) Class V chitinase receptors on the cell surface, while A-chain inhibits protein syn-

homologs with lectin activity, (4) Cyanovirin family, (5) EEA fam- thesis intracellularly via interacting with 28S ribosome, indicating

ily, (6) GNA family, (7) proteins with hevein domains, (8) Jacalins, that the cellular cytotoxicity of MLs may require both the A- and

(9) proteins with legume lectin domains, (10) LysM domain, (11) B-chains (Hoessli and Ahmad, 2008). Recently, accumulating data

Nictaba family (formerly Cucurbitaceae phloem lectins), (12) Ricin- have demonstrated that MLs (mainly referring to ML-I and ML-II)

B family (Van Damme et al., 2008) (see in Table 1). Amongst possess anti-proliferative activities toward various types of can-

the above-mentioned lectin families, Ricin-B family, proteins with cer cells (e.g., human acute lymphoblastic leukemia cells, human

legume lectin domains and GNA family have been widely reported hepatocarcinoma cells, human A549 lung cancer cells and human

to have a number of links to many pathological processes, such as myeloleukemic U937 cells) (Fulda and Debatin, 2006; Hoessli and

cancer (Liu et al., 2010a). Ahmad, 2008).

On one hand, some plant lectins were previously used as sim- Moreover, ML-I was shown to possess more sensitivity to apo-

␣

ple tumor recognition tools to differentiate malignant tumors from ptosis induction by TNF- , which further suggests the cooperation

benign and the degree of glycosylation associated with metastasis between ML-I and TNF-family death receptors in determining can-

(Mody et al., 1995). In the recent years, they have been developed cer cell death (Pryme et al., 2006; Hoessli and Ahmad, 2008).

for utilization as sophisticated microarray for better recognizing In addition, ML-I was found to induce apoptosis by activating

malignant tumors in diagnosis and prognosis of cancer (Gupta et al., caspase-8 via the extrinsic apoptotic pathway, but independent

2010). On the other hand, these lectins have been well-known to of death receptor pathway in Jurkat leukemic T cells (Bantel

possess antitumor activities, via targeting programmed cell death et al., 1999). Interestingly, ML-I was shown to potentiate the

(PCD), which is a cell-intrinsic mechanism for eliminating harm- effects of chemotherapeutic drugs such as etoposide, further

ful cells and maintaining homeostasis, including apoptosis and supporting the possibility of ML-I utilized for cancer therapy

autophagy (Li et al., 2009). Apoptosis (from Greek ‘apo’, mean- (Bantel et al., 1999).

ing from, and ‘ptosis’, meaning falling) or type I programmed cell Additionally, Korean mistletoe lectin (KML), belonging to ML-I,

death, is a complex but highly deﬁned cellular program of cell death has been further demonstrated to induce apoptosis by a mitochon-

(Cotter, 2009). Autophagy, a term from Greek “auto” (self) and drial pathway independently of p53 in hepatocarcinoma cells (Lyu

“phagy” (to eat), refers to an evolutionarily conserved, multi-step et al., 2002). In good agreement with this report, another study

lysosomal degradation process in which a cell degrades long-lived has recently shown that ML-I induces apoptosis by the break-

proteins and damaged organelles (Wang et al., 2011b). Within the down of mitochondrial membrane potential (MMP) and caspase-3

context of cancer, there are multiple connections between apo- activation independently of p53, but apoptosis-associated factor-1

ptosis and autophagy that may jointly seal the ultimate fate of (Apaf-1)-dependent pathway (Hostanska et al., 2003). Also, ML-I

cancer cell (Giansanti et al., 2011). Hitherto, several plant lectins has been shown to alter MMP; thereby resulting in cytochrome c

such as MLs and Ricin have been well-studied to possess anti- release and increase of the levels of reactive oxygen species (ROS)

proliferative and apoptosis-inducing activities toward cancer cells in Hep3B cells (Lavastre et al., 2002).

(De Mejía and Prisecaru, 2005). Besides, other lectins such as ConA Furthermore, ML-I A-chain has been found to activate JNK,

and PCL can result in autophagic cell death after internalization or which can promote translocation of some pro-apoptotic proteins

binding certain sugar-containing receptors on the surface of cancer belonging to Bcl-2 family such as Bax and Bad to the mitochondria

cells (Lei and Chang, 2007). Amazingly, although plant lectins were through phosphorylation of 14-3-3. Subsequently, phosphoryla-

ﬁrstly described approximately 30 years ago, our molecular under- tion of 14-3-3 may lead to the dissociation of BAX and BAD from

standing of it still remains to be clariﬁed. Therefore, this timeline this protein (Sunayama et al., 2005). As phosphorylated Bcl-2

covers a historic viewpoint of plant lectin research, with a speciﬁc can inhibit apoptosis, ML-I activates TNF-␣, which subsequently

highlight on a series of the key events that may spark off a rising induces dephosphorylation of Bcl-2 protein, suggesting that ML-

prominence in cancer research (Fig. 1). I induces apoptosis by down-regulation of Bcl-2 independently

In this review, we summarize the updated research of repre- of p53- and p21-mediated pathways (Lyu et al., 2002). Following

sentative plant lectins that may lead to programmed death via dephosphorylation, these pro-apoptotic proteins are translocated

targeting apoptotic and autophagic pathways in various types of to the mitochondria, where they can heterodimerize with Bcl-2,

cancer cells. In addition, we also demonstrate the potential thera- resulting in cytochrome c release, caspase activation and cancer cell

peutic roles of plant lectins at preclinical and clinical trial stages for apoptosis. Intriguingly, Chinese mistletoe lectin-I (CM-I) has been

cancer drug discovery. reported for the ﬁrst time to bear anti-neoplastic activity toward

colorectal cancer by downregulating miR-135a&b expression and

upregulating the expression of their target gene adenomatous poly-

2. Molecular mechanisms of Ricin-B family-induced posis coli (APC); thereby, decreasing the activity of downstream

apoptosis Wnt pathway (Li et al., 2011b).

Besides the apoptosis-inducing activities of ML-I, ML-II has also

2.1. Mistletoe lectins been found to possess marked anti-proliferative and apoptosis-

inducing activities, by activating MAPK signaling, implicated in

Mistletoe lectins (MLs), well-studied type II ribosome- ERK and p38, meanwhile altering cellular signaling pathways that

inactivating proteins (RIPs II), were ﬁrstly isolated from European may modulate the apoptotic response (De Mejia and Dia, 2010).

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Table 1

The classiﬁcation of plant lectins.

Representative lectin Abbreviation Family Sugar-binding speciﬁcity Structure

Agaricus bisporus agglutinin ABA Agaricus bisporus agglutinin homologs Galactose 1Y2T (PDB)

Amaranthins

Chitinase-related agglutinin CRA Class V chitinase homologs with lectin activity High-mannose N-glycans

Cyanovirin-N CV-N Cyanovirin family Mannose 2JZJ (PDB)

Euonymus europaeus agglutinin EEA EEA family Mannose/galactose

Polygonatum cyrtonema lectin PCL GNA family Mannose/sialic acid 3A0C (PDB)

Wheat germ agglutinin WGA Proteins with hevein domains N-acetyl-d-glucosamine 2UVO(PDB)

Jacalin JAC Jacalins Mannose 3P8S (PDB)

Concanavalin A ConA Proteins with legume lectin domains d-mannose 3D4K (PDB)

LysM domain

Cucurbitaceae phloem lectin CPL Nictaba family

European mistletoe lectin ML-I Ricin-B family Beta-galactose 1M2T (PDB)

Fig. 1. The timeline: a history of plant lectins for cancer research.

In addition, ML-II has been reported to induce apoptosis via acti- toward molt-4 human lymphocyte and malignant melanoma cells

vating SAPK/JNK and p38 pathways, as well as via inhibiting (De Mejia et al., 2003).

ERK1/2 pathway in human monoblastic leukemia U937 cells (Pae

et al., 2001). And, SEK/JNK signaling pathway has been found to 2.2. Other Ricin-B family lectins

be involved in apoptosis induction toward human hepatocarci-

noma cells (Pae et al., 2001). More importantly, Korean mistletoe Ricin, belonging to Ricin-B family, was reported to induce

lectin, belonging to ML-I, has been reported to kill COLO cells apoptotic cell death through upregulating caspase-8 and its down-

in a time- and dose-dependent manner by activating caspase- stream caspase 3/7 in L540 Hodgkin’s lymphoma cells (Polito

2, -3, -8, and -9 and decreasing expression of anti-apoptotic et al., 2009). Additionally, RBA could inhibit the proliferation of

␬ ␬

nuclear factor- B (NF- B), X-linked inhibitor of apoptosis pro- human promyelocytic leukemia cell line (HL-60 cells) via cytotoxic

tein (XIAP), and Akt/protein kinase B (Khil et al., 2007). Without mechanisms involving caspase activation and apoptosis (Miyoshi

adequate data of the antitumor mechanisms of ML-III, it has et al., 2001). And, Rice bran agglutinin (RBA) had effects on

been reported to possess anti-proliferative and inhibitory activities chromatin condensation, nuclear fragmentation, DNA release, and

Fig. 2. Molecular structures of three representative plant lectins (A) mistletoe lectin-I (ML-I), the representative Ricin-B family lectin; (B) Concanavalin A (ConA), the

representative legume lectin; (C) Polygonatum cyrtonema lectin (PCL), the representative GNA family lectin.

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externalization of membrane phosphatidylserine in human can upregulate COX-2 expression and downregulate Akt expres-

monoblastic leukemia U937 cells (Kim et al., 2003). Moreover, Abrin sion via IKK/NF-␬B-dependent pathway in U87 glioblastoma cells

could trigger apoptotic death via a mitochondrial pathway toward (Proulx-Bonneau et al., 2010; Sina et al., 2010). Moreover, another

various types of cancer cells such as Jurkat, CCRF-HSB-2, MOLT-4, report has recently veriﬁed that ConA selectively induces apoptosis

RPMI8402, and BALL-1 cells (Bagaria et al., 2006). Also, Abrin was in p53-null cells and shows no effect to normal cells retaining

found to induce apoptosis by stimulating caspase-3 expression and p53. During this process, p73, a member of p53 family, played an

blocking Bcl-2 expression in murine Dalton’s Lymphoma Ascites essential role by rendering the Bax/Bcl-2 ratio more favorable to

(DLA) cells (Ramnath et al., 2009). Most recently, Abrin has been apoptosis, and inhibiting the survival Akt pathway as well as acti-

to trigger apoptosis in Jurkat cells in a caspase-dependent manner, vating Foxo1a-Bim signaling in both ovarian cancer SKOV3 and

and can induce programmed necrosis in U266B1 cells in a caspase- Li-Fraumeni syndrome MDAH041cells (Ruhul Amin et al., 2007).

independent manner, even when there was ROS production and Interestingly, in SKP53 and TR9-7 expressing wild-type p53 cells,

loss of MMP. These results have revealed that Abrin-mediated inhibition of p53 function rendered these cells sensitive to ConA

necrosis can involve lysosomal membrane permeabilization and and its apoptotic mechanism is the similar Foxo1a-Bim signaling

release of cathepsins from the lysosomes. Importantly, it has been pathway (Ruhul Amin et al., 2010).

suggested that Abrin-mediated death pathway appears to depend However, to date, only one report has demonstrated that ConA

on which of the two events occurs ﬁrstly: lysosomal membrane can induce autophagic cell death in hepatoma cells through a

permeabilization or loss of MMP that may decide cancer cell death mitochondria-mediated pathway. After associating with mannose

by apoptosis or necrosis (Bora et al., 2010). moiety residing on the cell membrane glycoprotein, ConA was pref-

As discussed above, MLs and other Ricin-B family lectins (Ricin, erentially internalized to the mitochondria via clathrin-mediated

RBA and Abrin) bear apoptosis-inducing activities toward cancer endocytosis, and then the autophagic cell death was initiated

cells by targeting different stages of apoptotic pathways (Fig. 3). (Chang et al., 2007). Supportive of the notion, marked morpholog-

Due to their anti-tumor effects, Ricin-B family are being gradually ical changes were observed after ConA intervention, and several

unraveled its complex molecular mechanisms in vitro, which may characteristics including LC3-II formation, Bcl2/adenovirus E1B

provide a promising insight into elucidating more details for their 19 kDa-interacting protein 3 (BNIP3) induction, double-layer vesi-

potential therapeutic applications. cles and acidic vesicular organelle are detected. Subsequent studies

demonstrated that this autophagic death was BNIP3-mediated

mitochondrial autophagy (Lei and Chang, 2009). Furthermore, in

3. Molecular mechanisms of proteins with legume lectin proteomics research, ConA was treated into Chang liver cells and

domains-induced apoptosis or autophagy MHCC97-H cells and some up-regulated glycoproteins such as Heat

shock protein 96 (HSP96) were associated with liver cancer, indi-

3.1. Concanavalin A cating that they may be used as the key biomarkers for cancer

diagnosis (Xu et al., 2007). Also, ConA was used to modify mag-

Proteins with legume lectin domains are well-known to possess netic nanoparticles for selective separation of glycoptoteins and

a wide range of biological functions such as anti-tumor, anti-viral, application to glycoproteomics in hepatocellular carcinoma cells,

and anti-fungal activities. ConA, the ﬁrst reported legume lectin, suggesting that it may provide convenient and efﬁcient enrich-

has been drawing a rising attention owing to its anti-tumor activ- ment approach for glycoproteins and are promising candidates for

ity (Fig. 2B). In the year of 1995, ConA was reported to induce large-scale glycoproteomic research (Tang et al., 2010). Although

apoptosis in balb/c 3T3 (3T3) and diploid human gingival ﬁbrob- several pre-clinical uses of ConA have been proposed, these results

lasts (HGF), associated with carbohydrate-binding property of are still preliminary, and further pre-clinical studies of ConA should

ConA (Kulkarni and McCulloch, 1995). Recent studies have demon- be urgently needed before clinical therapies.

strated that ConA bears apoptosis-inducing activities, and initiation

of this apoptotic cell death can be mediated by mitochondria 3.2. Other proteins with legume lectin domains

(Liu et al., 2009c; Li et al., 2010). Additionally, it was suggested

that after ConA administration, human melanoma A375 cells and Besides, other proteins with legume lectin domains are reported

human hepatocellular liver carcinoma HepG2 cells could commit to possess signiﬁcant anti-proliferative and apoptosis-inducing

to death through a mitochondria-mediated apoptotic pathway: activities toward a variety of types of cancer cells. A series of sub-

MMP collapse, cytochrome c release and caspase 9/3 activation sequent studies have demonstrated that Dark red kidney bean

were detected, and thus eventually culminating in apoptosis (Liu hemagglutinin (PHA-E) can exert an anti-proliferative activity

et al., 2009d, 2010c). In addition, SHPS-1 has been reported for toward leukemia L1210 cells (Xia and Ng, 2006). And, small glossy

the ﬁrst time to be regarded as an important receptor for ConA. black soybean lectin can impede proliferation of breast cancer MCF-

This lectin directly binds to the extracellular region of SHPS-1 7 cells and hepatoma HepG2 cells (Lin et al., 2008). Recently, some

and this interaction mediates ConA-dependent activation of Akt reports have demonstrated that Del Monte banana lectin retards

and secretion of MMP-9, indicating that SHP-2 is recruited to proliferation of L1210 cells and HepG2 cells (Cheung et al., 2009).

SHPS-1 upon ConA-stimulation required for ConA-dependent Akt And, extralong autumn purple bean lectin can inhibit prolifera-

activation. Thus, it is suggested that activation of both Akt and tion of HepG2 cells by inducing production of apoptotic bodies

extracellular-signal regulated kinase (ERK) may be required for (Lam and Ng, 2011). Also, French bean hemagglutinin has been

the increased secretion of MMP-9 by ConA (Biswas et al., 2006). shown to induce breast cancer MCF-7 cell apoptosis (Lam and Ng,

More importantly, SHP-2 has been reported for the ﬁrst time to 2010). Moreover, a lectin (named AMML) from the roots of Astra-

be required for the augmented production, secretion, and prote- galus mongholius has been reported to induce apoptosis toward

olytic activation of MMP-2 by ConA-stimulation in cancer cells. human carcinoma cells (HeLa), human osteoblast-like cells (MG63)

Within this context, SHP-2-dependent activation of Ras signaling and human leukemia cells (K562) (Yan et al., 2009). In addition,

as well as the dual mitogen-activated protein kinase (MAPK) sig- a legume lectin named Sophora ﬂavescens lectin (SFL) has been

naling pathways involved in ERK and p38 are required for the reported to induce tumor cell death through a caspase-dependent

activation of MMP-2 secretion by ConA (Ruhul Amin et al., 2003). apoptotic pathway, and its apoptotic mechanisms are speculated

Most recently, ConA has been reported that cell surface carbohy- to be the death-receptor pathway (Liu et al., 2008b). And, another

drate structures account for MT1-MMP intracellular signaling that legume lectin with sialic acid-binding speciﬁcity from Phaseolus

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Fig. 3. Plant lectins induce cancer cell death via targeting programmed cell death (PCD) signaling network.

coccineus L. seeds possesses an anti-proliferative activity. This lectin accompanied with caspase-9, caspase-8 and caspase-3 activation in

induced the caspase-dependent apoptosis in L929 cells, and the L929 cells, suggesting that the apoptotic mechanism is a caspase-

anti-neoplastic activity of this lectin was decreased abruptly when dependent pathway (Zhang et al., 2010). In addition, some reports

the sialic acid speciﬁcity was completely inhibited, which indicates have recently shown that PCL induces apoptosis in A375 cells. The

that this sugar-binding speciﬁcity may be the main reason spark- mechanism of apoptosis following treatment with PCL involve reg-

ing off the anti-neoplastic activity and apoptosis (Chen et al., 2009). ulation of Bax, Bcl-XL and Bcl-2 proteins, which then cause collapse

Together, these above-mentioned results would provide new clues of MMP, leading to cytochrome c release and caspase activation

for exploring the molecular mechanisms of PCD induced by legume (Liu et al., 2009b). The treatment with PCL also abrogated the glu-

lectins for cancer research (Fig. 3). tathione antioxidant system, and induced mitochondria to generate

massive ROS accumulation, which subsequently result in p38 and

4. Molecular mechanisms of Galanthus nivalis agglutinin p53 activation, indicating that PCL induces apoptosis through a

(GNA) family-induced apoptosis and/or autophagy mitochondria-mediated ROS-p38-p53 pathway (Liu et al., 2009b).

Moreover, some studies reported that PCL led to apoptosis in L929

4.1. Polygonatum cyrtonema lectin cells. Subsequently, inhibition of Ras promoted L929 cell death,

suggesting that Ras-Raf signaling pathway plays the key negative

Polygonatum cyrtonema lectin (PCL), a mannose/sialic acid lectin regulator in PCL-induced apoptosis. Furthermore, Class I PI3K-Akt

belonging to GNA family, was ﬁrstly isolated from Polygonatum cyr- signaling pathway was shown to play the negative regulator in PCL-

tonema Hua (Liu et al., 2009a; Li et al., 2011a) (Fig. 2C). Hitherto, PCL induced apoptosis (Liu et al., 2010b). It is suggested that PCL induces

has drawn many interests for its anti-tumor activities toward HeLa, apoptosis via blocking Ras-Raf and PI3K-Akt signaling pathways in

MCF-7, A375 and L929 cells, but with concomitant low toxicity to L929 cells.

the normal cells (Wang et al., 2011a). Importantly, accumulating Furthermore, PCL was reported to induce autophagic cell

evidence has revealed that PCL can induce cancer cell death tar- death via a mitochondria-mediated pathway in A375 cells. Sub-

geting PCD pathways, such as the caspase-dependent pathways, sequently, PCL-induced autophagic death was further conﬁrmed

mitochondrial ROS-p38-p53 pathway, Ras-Raf and PI3K-Akt path- to be a mitochondrial-mediated ROS-p38-p53 pathway (Liu et al.,

ways (Wang et al., 2011a). Firstly, PCL was reported to possess 2009a,b). Additionally, PCL induced autophagic cell death in L929

anti-proliferative and apoptosis-inducing activities toward HeLa cells. Subsequently, inhibition of Ras could promote L929 cell

cells (Liu et al., 2008a). And, PCL could induce human breast cancer death, suggesting that Ras-Raf pathway plays the key negative

MCF-7 cell apoptosis with caspase participation (Liu et al., 2009e). regulator in PCL-induced autophagic cell death. And, PI3K-Akt path-

To further conﬁrm whether caspases play the key roles in PCL- way was reported to play the negative regulator in PCL-induced

induced cancer cell apoptosis, PCL was found to induce apoptosis, autophagic cell death (Wang et al., 2011a; Liu et al., 2010b).

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Table 2

The potential therapeutic applications of plant lectins.

Lectin Cancer type Effect Stage Reference

ConA Murine B16 melanoma cells Cytotoxicity/tumor inhibition Pre-clinical De Mejía and Prisecaru (2005),

Lei and Chang (2007)

Murine BALB/c hepatoma ML-1 and Autophagic death

colon CT-26 cells; human

hepatocellular liver carcinoma Huh-7

cells and HepG2cells

PHA-L Murine non-Hodgkin lymphoma Cytotoxicity/tumor inhibition Pre-clinical Liu et al. (2010a), De Mejía and

tumor, and apoptosis Prisecaru (2005)

Human melanoma cells, human

rhabdomyosarcoma cells, human

leiomyosarcoma cells,

SP2 myeloma cells, Lox-2

Ab-producing hybridoma cells,

B-DLCL human large B-cell lymphoma

cells

ML-I Murine non-Hodgkin lymphoma (NHL) Cytotoxicity/tumor inhibition Pre-clinical Hoessli and Ahmad (2008), Liu

tumors, human ovarian cancer in SCID and apoptosis et al. (2010a)

mice, chemically induced urinary

bladder cancer in mice, murine

melanoma, urinary bladder carcinoma

MB49, and B16-BL6 melanoma cells

Human molt-4 lymphocyte cells, Cytotoxicity/tumor inhibition Clinical (stages II–III) De Mejía and Prisecaru (2005),

human cervical carcinoma HeLa, and and apoptosis Liu et al. (2010a)

human breast carcinoma MCF-7 cells

Therefore, the evidence demonstrates that PCL induces cancer activation. Moreover, POL treatment led to MMP collapse,

cell autophagy via promoting ROS-p38-p53 pathway, as well as cytochrome c release and subsequent activations of caspase-9 and

blocking Ras-Raf and PI3K-Akt signaling pathways. Interestingly, caspase-3. Interestingly, POL could also amplify the apoptotic effect

␣

PCL-induced autophagic cell death and apoptosis can connect with of TNF- at low concentrations in L929 cells (Karasaki et al., 2001).

each other to participate in leading to cancer cell death via promot- With the complex molecular mechanisms of GNA family-

ing a mitochondria-mediated ROS-p38-p53 pathway, as well as via induced PCD becoming better elucidated, there is no doubt that

blocking Ras-Raf and PI3K-Akt pathways (Wang et al., 2011a). new therapeutic strategies would be developed into targeting

apoptotic and autophagic cell death pathways for cancer thera-

peutics. Moreover, subsequent pre-clinical and clinical trials into

4.2. Other GNA-related lectins

the mechanisms of actions would help us understand the possible

therapeutic effects of GNA family as antitumor agents (Fig. 3).

Other GNA-related lectins are widely reported to possess

apoptosis-inducing activities toward cancer cells. Garlic lectin, iso-

lated from garlic (Allium sativum L.) bulbs, was reported to possess 5. Possible therapeutic implications of plant lectins in

cytotoxic effects in human tumor cells. This lectin was able to cancer

strongly inhibit DNA synthesis in human U937 and HL60 cells and

induced apoptosis at a low concentration (Karasaki et al., 2001). With the accumulating exploration of mechanisms of plant

Subsequently, PCL and the other two GNA-related lectins, OJL and lectins in cancer, they have been widely used as candidate anti-

LNL were reported to possess inhibitory effects on the growth of tumor drugs in human cancers in vitro; more importantly, some

MCF-7 cells. The three lectins bear three mannose-binding sites in of them have been further applied into the pre-clinical and clin-

which LNL could possess three conserved motifs ‘QXDXNXVXY’; ical therapies in ﬁghting for human cancers (Gupta et al., 2010;

OJL possesses two such motifs and PCL possesses only one motif Thies et al., 2005). Plant lectins from Ricin-B family and proteins

(Liu et al., 2009e). The differences of growth inhibition effects on with legume lectin domains have been well-known to induce can-

MCF-7 cells were consistent with the number of conserved motifs cer cell programmed death, referring to apoptosis and autophagic

of lectins, and the mutations of the amino acids in the sugar-binding cell death, in vivo.

active center might result in the phylogenetic evolution and diver- Within the context of different types of murine in situ tumor

siﬁcation of carbohydrate-binding speciﬁcities at molecular level models, Ricin-B family, especially ML-I possess apoptosis-inducing

(Yu et al., 2011). Thus, the GNA-related lectins with more mutated effects on many types of cancers (see in Table 2). Additionally,

sites can bind to more types of sugar chains or carbohydrate- proteins with legume lectin domains such as ConA and Phase-

containing receptors on the surface of tumor cells, which may olus vulgaris lectin (PHA) can also induce apoptotic cell death

activate more cell death signaling pathways (Liu et al., 2009e; Yu toward various types of cancers; more interestingly, besides

et al., 2011). Additionally, another mannose-binding lectin (named apoptosis-inducing effect, ConA induces autophagic cell death in

CML), a possibly GNA-related lectin, was isolated from Clematis hepatocarcinoma (see in Table 2). Accordingly, these results may

montana Buch.-Ham stem (Ranunculaceae) and reported to induce provide more systematic evidence for better guiding the subse-

L929 apoptosis through the caspase-dependent and death-receptor quent clinical trials.

pathways (Peng et al., 2009). In clinical trials, ML-I has been widely utilized as potential anti-

Recently, POL, a mannose-binding speciﬁc GNA-related lectin, neoplastic drugs or adjuvant therapeutic agents. Notably, this lectin

has been reported to possess apoptosis-inducing activities toward has been indicated for the reduction of treatment-associated side-

L929 cells in a caspase-dependent pathway (Liu et al., 2009f). POL effects as adjuvant agents during chemotherapy and radiotherapy

induced cell death through the death-receptor apoptotic path- in Europe for several decades (Liu et al., 2010a). Recently, Euro-

way by increasing the levels of FasL and Fas-Associated protein pean mistletoe lectins have been tested for the safety and efﬁcacy

with Death Domain (FADD) proteins and results in caspase-8 during post-surgical after care of primary intermediate to high-risk

Author's personal copy

1448 L.-l. Fu et al. / The International Journal of Biochemistry & Cell Biology 43 (2011) 1442–1449

malignant tumor patients (stages II–III), comparing with untreated (Boston University) and Ming-wei Min (University of Cambridge)

control group. And, the long-term treatment of these lectins are for their critical reviews on this manuscript. We also thank Jun-

reported to be safe and without any further tumor enhancement jie Liu (Tsinghua University), Huai-long Xu and Qi-jia Yu (Sichuan

(De Mejía and Prisecaru, 2005; Liu et al., 2010a). Additionally, University) for their good suggestions on this work. Additionally,

mistletoe lectins have also been studied to be prepared as an aque- this work was supported by the grants from the National Natural

ous injectable solution, which beneﬁts for the survival rates of Science Foundation of China (no. 30970643), Young teacher’s fund

patients, the anti-tumor activities and low toxicity proﬁles in clin- of Sichuan University (no. 2010SCU11066) and the Science Foun-

ical trials. More importantly, recombinant ML-I has also been used dation for Post Doctorate Research of China (no. 20110491725).

to evaluate its safety proﬁle, dose-limiting toxicity and maximum

tolerated dose of the administration for cancer patients at clinical

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