Implications of apoptosis in cancer immunotherapy

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Advances in Bioscience and Biotechnology, 2012, 3, 679-685 ABB

http://dx.doi.org/10.4236/abb.2012.326088 Published Online October 2012 (http://www.SciRP.org/journal/abb/)

Implications of apoptosis in cancer immunotherapy*

Gregory Lee, Bixia Ge

UBC Centre for Reproductive Health, University of British Columbia, Vancouver, Canada

Email: [email protected]

Received 14 August 2012; revised 20 September 2012; accepted 28 September 2012

ABSTRACT

Inhibitions or blockages of ligand-receptor interac-

tions on cancer cell surfaces by exogenous compete-

tors or antibodies often result in apoptosis or “pro-

grammed cell death”. The underlying mechanisms of

action for cellular apoptosis depend greatly on the

molecular nature of specific ligand-receptor interac-

tions and the signal transduction pathways involved.

Two such unrelated systems which are potentially

involved in apoptosis of cancer cells are described in

this review. They are, respectively, gonadotropin-

releasing hormone (GnRH) receptor and cancerous

immunoglobulins, or CA215, both of which are widely

expressed on the surface of cancer cells from diversi-

fied tissue origins. Bindings of GnRH or its decapep-

tide analogs as ligands to GnRH receptor were known

to induce apoptosis of several extrapituitary cell types

in gonadal tissues, as well as different cancer cells.

Monoclonal antibodies against the GnRH receptor of

cancer cells were shown to induce apoptosis, similar

to the action of GnRH analogs. In contrast, RP215

monoclonal antibody reacts specifically with the car-

bohydrate-associated epitope of cancerous immu-

noglobulins and is known to induce apoptosis of can-

cer cells in vitro. It also causes growth inhibition of

tumor cells in nude mouse experimental models. Elu-

cidations of the specific mechanisms of apoptosis in

cancer cells of these two molecular interaction sys-

tems will not only lead to a better understanding of

cancer biology but also benefit patients in cancer

monitoring and therapy.

Keywords: Apoptosis; GHR106; RP215; CA215;

Pan-Cancer Biomarker; GnRH Receptor

1. INTRODUCTION

1.1. Gonadotropin-Releasing Hormone versus

Gonadotropin-Releasing Hormone Receptor

in Cancer Cells

It has been known for decades that gonadotropin-releas-

ing hormone (GnRH), from the hypothalamus, acts as the

ligand to the GnRH receptor, located in the anterior pi-

tuitary gland, to trigger the release of luteinizing hor-

mone (LH) and follicle stimulating hormone (FSH) [1].

Both LH and FSH are essential hormones for sexual

maturation and differentiation of gonadal tissues in both

sexes, which result in the production and release of either

sperm (male) or oocytes (female) for reproduction [1].

It was later observed that GnRH receptor was also

found in a number of extrapituitary tissues/organs, espe-

cially in reproductive tissues. This extrapituitary GnRH/

GnRH receptor system serves completely different phy-

siological functions [1,2]. Basically, GnRH and GnRH

receptor in these tissues or cells are expressed in auto-

crine/paracrine regulations of cellular growth, apoptosis

or differentiation [3]. Under certain normal physiological

conditions, apoptosis can be induced through combined

expressions of GnRH and GnRH receptor in a given cell

type in response to the stimuli of surrounding cellular

conditions [3,4]. In the case of cancer cells, GnRH and

GnRH receptor are universally expressed and regulated

irrespective of their tissue origins [3-5].

Apoptosis can be readily induced with exogeneous

GnRH or its analogs to cancer cells [1,2]. In view of the

fact that the native neuroendocrine hormones, GnRH I

and GnRH II, are relatively short in circulation half-life

(~minutes), GnRH analogs were synthesized and utilized

as a substitute of native GnRH and demonstrated a

somewhat longer half-life (~hours) in circulation. These

GnRH analogs were further classified as agonists and

antagonists, depending on their hormone actions in the

pituitary gland [5,6].

Although both the agonists and antagonists have com-

parable or better affinities to GnRH receptor or longer

half-lives than that of GnRH, their respective biological

actions are completely opposite to each other. While

GnRH agonists show similar functions as those of GnRH,

GnRH antagonists can function to inhibit or down-regu-

late LH and FSH release from the pituitary cells [7].

However, in the case of cancer cells, apoptosis can be

induced whether by native GnRH, GnRH agonists, or

GnRH antagonists, in vitro [8,9].

*Conflict of interest: Gregory Lee is a co-founder of Vancouver Bio-

tech Ltd. Recently, monoclonal antibodies (mAbs) against the

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G. Lee, B. Ge / Advances in Bioscience and Biotechnology 3 (2012) 679-685

680

GnRH receptor, especially those specific to the extra-

cellular domain of N1-29 synthetic peptide, have been

successfully generated and characterized [10,11]. These

mAbs can be considered as long acting and high mo-

lecular weight GnRH analogs with an average half-life of

5 - 21 days in circulation.

Through extensive comparative studies with GnRH

analogs, it was concluded that anti-GnRH receptor mAb,

GHR106, was essentially identical to GnRH or its ana-

logs in terms of their respective biological actions [8,12].

Apoptosis can be induced to cancer cells in vitro upon

incubation of GHR106 mAb in cultured cancer cells [13].

The apoptotic mechanisms of action of GHR106 mAb

were studied through gene expression and regulation

studies [12]. The results were then compared with those

observed previously for the GnRH analogs. The study

results are summarized in this review. Our aim is to

evaluate if GHR106 mAb can be a suitable substitute for

GnRH agonists and can be used as a long-acting anti-

cancer drug, following humanization and clinical studies

[13].

1.2. Cancerous Immunoglobulins versus RP215

in Cancer Cells

It has been known for two decades [14,15] that immu-

noglobulins are expressed by cancer cells and certain

normal cells other than B cells in humans [16]. It was

later demonstrated in several laboratories that cancer

cell-expressed immunoglobulins are required for the

growth and proliferation of cancer cells in vitro and in

vivo [14,15]. However, the etiology of the expression of

cancerous immunoglobulins is still not fully understood.

In 2008, a mAb designated as RP215 was shown to react

mainly with the carbohydrate-associated epitope of can-

cer cell-expressed immunoglobulins [17,18]. Through

extensive matrix-assisted laser desorption/ionization time-

of-flight mass spectrometry (MALDI-TOF MS) and pro-

tein BLAST studies, it is now established that RP215

mAb’s specific “sugar” epitope can be detected specifi-

cally in a number of glycoproteins, generally known as

CA215. CA215 represent a group of glycoproteins con-

sisting of immunoglobulins (42%), T-cell receptors (6%)

[19], cell adhesion cells (8%), MHC molecules (5%) and

several others [12,18]. It was further demonstrated that

the RP215-specific epitope is not found in immunoglobu-

lins derived from normal B cells [18,20].

CA215 glycoproteins consist of both membrane-bound

and soluble (secreted) forms in cancer cells [18]. The

RP215-specific epitope found in CA215 was shown to be

universally expressed on almost all cancer cells [20].

Similar to the relationship between GHR106 mAb and

GnRH receptor in cancer cells, RP215 mAb was shown

to induce apoptosis and complement-dependent cytotox-

icity (CDC) reactions to many types of cancer cells [19].

Attempts have been made to elucidate the mechanisms of

action regarding the induction of apoptosis through gene

regulation and expression studies [12]. These results are

briefly summarized in this review.

2. APOPTOSIS AND GENE

REGULATION OF CANCER CELLS BY

GHR106 MONOCLONAL ANTIBODY

Comparable Biological Activities between

GHR106 and Gonadotropin-Releasing

Hormone Analogs

As explained in the previous section, GHR106 mAb was

generated against the extracellular domain (N1-29 amino

acid residue) of the human GnRH receptor [10]. It is in

fact a high molecular weight equivalent of GnRH ana-

logs (80 kDa vs 1.2 kDa) in terms of its relative bio-

logical actions [11], except with a longer half-life than

the latter (5 - 21 days vs hours).

Similar to GnRH or its analogs, apoptosis of cancer

cells can be induced upon treatment with GHR106 mAb

for 24 to 48 hours. Dose-dependent growth inhibitions of

implanted tumors was also demonstrated with GHR106

mAb, as well as GnRH analogs in nude mouse animal

models [13].

The mechanisms of actions of GnRH or its analogs

(agonists and antagonists) to induce apoptosis of cancer

cells have been studied extensively since two decades

ago [1-4]. Generally speaking, upon bindings of GHR106

or GnRH analog to GnRH receptor in cancer cells, major

changes in the gene expressions of OC-3-VGH ovarian

cancer cells were observed [11,21]. The results of such

parallel studies with a number of genes involved in the

growth regulations of cancer cells are summarized in

Table 1 for comparison.

Based on the results of this study, both GHR106 mAb

and GnRH antagonist (Antide, in this case) were found

to exhibit identical biological actions on the expressions

of a number of genes which are involved in the growth

and proliferation of cancer cells [22]. Interestingly, both

GHR106 mAb and Antide (GnRH antagonist) cause con-

sistent down-regulation of the epidermal growth factor

(EGF) [8], the cell cycle regulator, cyclin D, and some of

the ribosomal genes involved in cellular protein synthesis,

such as L37 and P0, whereas up-regulation of another

cell cycle regulator, P21, was observed.

Terminal deoxynucleotidyl transferase dUTP nick end

labeling (TUNEL) assay [9] has been well established to

assess induced apoptosis of cultured cancer cells upon

incubation with either GHR106 mAb or GnRH analogs

(Antide) [12,13]. A number of cancer cell lines were used

for comprehensive analysis, including those of the pros-

tate (PC-3 and DU145), lung (A549), and breast (MDA-

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G. Lee, B. Ge / Advances in Bioscience and Biotechnology 3 (2012) 679-685 681

Table 1. Effect of treatments of cultured OC-3-VGH ovarian

cancer cells with various monoclonal antibodies or GnRH an-

tagonists on gene expressions.

GHR106 (10 μg/mL)

Gene RP215

(10 μg/mL) 10 μg/mL 20 μg/mL

Antide (GnRH

Antagonist)

(0.1 μg/mL)

GnRH NTa ↑ ↑ ↑

GnRH

receptor NT NC NC NC

IgG ↑a NT NT NT

NFKB1b ↑ NT NT NT

P0 ↓ ↓ ↓ ↓

P1 ↓ ↑ ↑ ↑

P2 ↓ NC NC NC

L37 NCa ↓ ↓ ↓

EGF NC ↓ ↓ ↓

c-fos ↓ NC NC NC

P21 ↓ ↑ ↑ ↑

Cyclin D ↓ ↓ ↓ ↓

aNT: Not Tested; NC: No Change; ↑ and ↓ indicate significant up and down

gene regulation, respectively when compared to that of GAPDH; bAb-

breviations used: NFKB1—nuclear factor kappa-B p105 subunit 1;

P0/P1/P2/L37—ribosomal proteins; EGF—epidermal growth factor; c-fos—

cellular proto-oncogene; P21—cyclin-dependent kinase inhibitor 1; cyclin

D—G1/S phase regulator protein.

MB-435). The percent of apoptotic cells upon 24 - 48

hour treatments of these ligands were statistically ana-

lyzed and presented in Table 2(a) for comparisons [12,

13]. It was clearly demonstrated that GHR106 mAb and

GnRH antagonist were found to have comparable effects

on the induced apoptosis of treated cancer cell lines.

3. APOPTOSIS AND GENE

REGULATION OF CANCER CELLS

BY RP215 MONOCLONAL ANTIBODY

3.1. Induced Apoptosis of Cancer Cells by RP215

Monoclonal Antibody

As mentioned, RP215 mAb was shown to react with the

carbohydrate-associated epitope of CA215 found on the

surface of different cancer cells, but rarely detected in

normal cells [13], except in hyperplastic epithelial cells

or cells of the immune privileged sites [16,23,24]. Pre-

vious studies by MALDI-TOF MS studies have indicated

glycoproteins expressed by cancer cells consist mainly of

immunoglobulins, derived from cancer cells [18]. These

cancerous immunoglobulins were known to be essential

growth factors for the growth and proliferation of differ-

ent cancer cells [16]. Therefore, it is reasonable to as-

sume that the masking of the surface bound immu-

noglobulins or CA215 can induce apoptosis following

RP215 mAb treatments of cancer cells.

Apoptosis of cancer cells can be induced not only by

RP215 mAb, but also by goat anti-human immunoglobu-

lin G (IgG) to cultured cancer cells [12,13,16]. Typical

studies with different cancer cell lines are summarized in

Table 2(b) with TUNEL assays. Compared to the nega-

tive control, apoptosis induced by RP215 mAb (1 - 10

µg/mL) and goat anti-human IgG to cultured cancer cells

were statistically significant [12,13,20]. A list of cancer

cell lines were employed in this comparable study in-

cluding those of the prostate (PC-3 and DU-145), lung

(A549), cervix (C33A), breast (MDA-MB-435) and

ovary (OC-3-VGH) [13]. Furthermore, apoptosis can be

induced at an antibody concentration as low as 1 µg/mL

[12,13]. Several RP215-related mAbs, including those of

the chimeric form, as well as those derived (RCA104,

RCA111) [12], were shown to have similar biological

actions in inducing apoptosis of OC-3-VGH cancer cells.

3.2. Effects of RP215 Monoclonal Antibody on

Gene Regulations of Cancer Cells

Apoptosis induced by RP215 mAb on cancer cells was

evaluated through gene expression studies [12,20,21]. By

means of semi-quantitative reverse transcription poly-

merase chain reaction (RT-PCR), the effects of RP215

mAb was analyzed through the expression of a number

of genes involved in cell growth regulations of cancer

cells. The results of such studies are summarized in Ta-

ble 1. It was generally observed that treatments of cancer

cells with RP215 mAb cause significant down-regulation

of several genes responsible for protein synthesis and

cell cycle control, whereas expressions of certain genes

involved in the expressions of immunoglobulins such as

IgG, nuclear factor kappa-B p105 subunit 1 (NFKB-1),

and the cellular signal transduction activator, c-fos, are

up-regulated [12].

4. DISCUSSION

In this mini review, two unrelated ligand/receptor sys-

tems were introduced to demonstrate the induced apop-

tosis of cultured cancer cells and the underlying molecu-

lar mechanisms investigated through regulation and ex-

pression of a number of genes relevant to cell growth and

proliferation [12,13]. In view of the universal expression

of the surface bound GnRH receptor and CA215 among

almost all cancer cells, GnRH receptor and CA215 can

be considered as pan-cancer biomarkers for any potential

diagnostic and therapeutic applications in human cancer

[12,13].

Both GHR106 and RP215 mAbs fulfill the criteria for

the development of anti-cancer drugs. First of all, the

antigen distributions are homgeneous and abundant on o

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G. Lee, B. Ge / Advances in Bioscience and Biotechnology 3 (2012) 679-685

Copyright © 2012 SciRes.

682

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Table 2. Effect of different antibodies on induced apoptosis of cultured cancer cells. (a) GHR106 monoclonal antibody and GnRH

analog (Antide) induces apoptosis of cultured cancer cells; (b) RP215 monoclonal antibody and goat anti-human IgG induces apop-

tosis of cultured cancer cells.

(a)

Cancer Cell Line (tissue) Incubation Time (hr) Antibody Antibody Concentration

(μg/mL)

% Apoptosis

(Negative Control)a

GHR106 10 40 ± 5 (9 ± 1)**

ChGHR106b 10 32 ± 4 (9 ± 1)**

PC-3 (prostate) 48

Antide (GnRH antagonist)0.1 35 ± 5 (9 ± 1)**

24 GHR106 10 32 ± 2 (12 ± 3)*

10 46 ± 9 (12 ± 3)*

DU-145 (prostate)

48 GHR106

20 42 ± 5 (7 ± 2)*

10 34 ± 10 (11 ± 5)*

A549 (lung) 24 GHR106

20 46 ± 11 (17 ± 3)*

10 31 ± 4 (7 ± 2)**

24 GHR106

20 45 ± 11 (6 ± 1)**

MDA-MB-435 (breast)

48 GHR106 10 39 ± 11(14 ± 13)*

aStatistical significance: *p < 0.05; **p < 0.01; bChGHR106: chimeric form of GHR106 mAb.

(b)

Cancer Cell Line (tissue) Incubation Time (hr) Antibody Antibody Concentration

(μg/mL)

% Apoptosis

(Negative Control)a

RP215 10 31 ± 7 (9 ± 1)*

ChRP215 10 38 ± 5 (9 ± 1)**

PC-3 (prostate) 48

Goat anti-human IgG 10 36 ± 4 (9 ± 1)*

RP215 10 32 ± 7 (12 ± 3)*

24

Goat anti-human IgG 10 46 ± 9 (12 ± 3)*

RP215 10 35 ± 8 (10 ± 1)*

20 43 ± 7 (7 ± 2)*

DU-145 (prostate)

48

Goat anti-human IgG 10 46 ± 9 (12 ± 3)*

RP215 10 30 ± 9 (11 ± 5)*

24

20 36 ± 12 (17 ± 3)*

RP215 10 36 ± 9 (13 ± 3)*

A549 (lung)

48

20 38 ± 10 (12 ± 2)*

C33A (cervix) 24 RP215 10 58 ± 11 (20 ± 3)*

RP215 20 37 ± 8 (6 ± 1)**

24

Goat anti-human IgG 10 44 ± 4 (7 ± 2)**

RP215 20 43 ± 8 (8 ± 3)**

MDA-MB-435 (breast)

48

Goat anti-human IgG 20 48 ± 15 (8 ± 3)**

24 RP215 10 51 ± 12 (18 ± 2)

RCA104b 1 35 ± 3 (6 ± 2)*

RCA111b 1 38 ± 4 (6 ± 2)**

OC-3-VGH (ovary)

48

RP215 1 45 ± 5 (6 ± 2)**

aS

tatistical significance: *p < 0.05; **p < 0.01; bSee reference #12: RCA104, RCA111 mAbs are generated by using CA215 as immunogen.

G. Lee, B. Ge / Advances in Bioscience and Biotechnology 3 (2012) 679-685 683

the cancer cell surface, but not generally found in normal

cells or tissues. Furthermore, CDC and antibody-de-

pendent cellular cytotoxicity reaction (ADCC) reactions

are effective with these two antibody-based drugs. Fi-

nally, cellular apoptosis by either mAb can be induced to

almost all cancer cells with known mechanisms of ac-

tion.

For the initial evaluations of anti-cancer drug candi-

dates, induced apoptosis on cancer cells may serve as a

meaningful indicator for future drug development. Nude

mouse animal models to demonstrate the growth inhibit-

tion of tumor cells upon drug treatment are also required

for “proof of concept”. In fact, for both GnRH/GnRH

receptor and RP215/CA215 systems, results of TUNEL

assay for apoptosis of cancer cells are so far consistent

with those of tumor growth inhibition in nude mouse

animal models [13].

4.1. GHR106 Monoclonal Antibody and

Apoptosis of Cancer Cells

The GnRH and GnRH receptor system, and their roles in

induction of apoptosis in cancer cells, have been known

for decades [1-4]. This system has been the basis of us-

ing GnRH agonists and antagonists for clinical therapy

of cancer in the prostate, breast, and ovary [7]. In addi-

tion, both GHR106 mAb and the GnRH analog (Antide)

were shown to have the same effects on the expression of

genes tested so far (see Table 1). However, the relatively

long half-life of GHR106 mAb (5 - 21 days) might be

beneficial clinically for use as anti-cancer drugs, when

compared with the GnRH analog, a small decapeptide,

which only has a half-life of a few hours. Humanized

forms of GHR106 mAb have been successfully gener-

ated for preclinical and clinical studies in the therapeutic

treatment of human cancer. As a potential antibody-based

anti-cancer drug, humanized GHR106 mAb has certain

intrinsic benefits over GnRH analogs besides its long

half-life. Both CDC and ADCC are effective in using

GHR106 mAb as anti-cancer drugs as mentioned previ-

ously. By comparison, as a synthetic decapeptide, the

GnRH analog has no parallel biological activities [7].

4.2. RP215 Monoclonal Antibody and Apoptosis

of Cancer Cells

Cancerous immunoglobulins are universally expressed

on the surface of all cancer cells of different tissue ori-

gins [14,15,25,26]. RP215 mAb, which reacts specifically

with the “sugar” epitope of cancerous immunoglobulins,

can be a suitable alternative for goat anti-human immu-

noglobulins to induce apoptosis, as shown in Table 2(b).

Both goat anti-human IgG and RP215 mAb can effec-

tively induce apoptosis of cancer cells [13,16,21]. This

observation would imply that the cancer cell surface may

be covered with bound cancerous immunoglobulins for

the unproven functions of cell growth, proliferation, and

communications [16]. Therefore, these immunoglobulins

and other bound CA215 may become unique targets for

RP215 mAb when used as an anti-cancer drug.

Bindings or blockages of cancerous immunoglobulins

with RP215 mAb to the cancer cell surface seem to affect

their critical biological functions for cell growth, result-

ing in induction of apoptosis of these cancer cells [16].

This phenomenon has become an advantage in terms of

the immunotherapy of human cancer with specific mAbs.

Dose-dependent inhibitions of tumor growth with RP215

mAb have been demonstrated with several nude mouse

animal models with implanted tumor cells from the ovary,

cervix or lung, respectively [13,27]. It is expected that

humanized forms of RP215 mAb can be a suitable can-

didate for the development of antibody-based anti-cancer

drugs for the immunotherapy of human cancer.

4.3. Effects of GHR106 and RP215 Monoclonal

Antibodies on Gene Expression of Cancer

Cells

The underlying mechanisms of these two mAbs inducing

apoptosis of cancer cells were investigated through gene

regulation and expression studies [12,13]. As summa-

rized in Table 1, both GHR106 mAb and GnRH antago-

nist react with the GnRH receptor and cause down-

regulation of epidermal growth factor and some ribo-

somal proteins required for protein synthesis. As clearly

indicated in this table, RP215 and GHR106 mAb do not

induce apoptosis of cancer cells through the same signal

transduction pathways [12].

RP215 mAb, which reacts mainly with cancerous im-

munoglobulins, was shown to induce apoptosis of cancer

cells, similar to anti-human immunoglobulins. This ob-

servation would suggest that apoptosis was induced on

cancer cells by both antibodies through similar or identi-

cal pathways or mechanisms of action [16]. Treatments

of this mAb with cultured cancer cells can result in

down-regulation of genes responsible for protein synthe-

sis and cell cycle regulations. Previously, it has also been

reported that transfection of cancer cells with SiRNA

related to IgG can result in apoptosis of cultured cancer

cells [25,26]. Furthermore, transfections of stable plas-

mid constructed with IgG-related small interfering RNA

(SiRNA) into cancer cells resulted in significant inhibit-

tion of cell growth and proliferation in vitro and in vivo

[25,26]. These experimental observations strongly sup-

port that cancerous immunoglobulins are required as

growth factors for the growth and proliferation of cancer

cells. This phenomenon may also provide important ra-

tionale for the induction of apoptosis upon treatments of

cancer cells with RP215 mAb. Therefore, it is reasonable

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G. Lee, B. Ge / Advances in Bioscience and Biotechnology 3 (2012) 679-685

684

to assume that humanized forms of RP215 mAb may

have the potential to be developed as an effective anti-

body-based anti-cancer drug with multi-indication for

different types of cancer in humans.

5. CONCLUSION

GHR106 and RP215 mAbs have been evaluated, with

respect to their actions, to induce apoptosis on cultured

cancer cells, of which the GnRH/GnRH receptor and

RP215/CA215 systems are universally and abundantly

present. It remains to be shown if the efficacy of these

two mAbs in humanized forms can be demonstrated

through extensive clinical studies for cancer therapy in

humans in the near future.

6. ACKNOWLEDGEMENTS

This work was supported in parts by NSERC-IRAP of Canada. The

excellent technical support of Suefay Liu from McGill University and

Vivian Wang from the University of British Columbia is acknowledged.

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