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
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

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-

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

G. Lee, B. Ge / Advances in Bioscience and Biotechnology 3 (2012) 679-685 682
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

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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