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GRP78 Induction in Cancer: Therapeutic and Prognostic Implications
Amy S. Lee
Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center,
University of Southern California Keck School of Medicine, Los Angeles, California
Abstract
Cancer cells adapt to chronic stress in the tumor microenvironment by inducing the expression of GRP78/BiP, a major
endoplasmic reticulum chaperone with Ca2+-binding and
antiapoptotic properties. GRP78 promotes tumor proliferation, survival, metastasis, and resistance to a wide variety of
therapies. Thus, GRP78 expression may serve as a biomarker
for tumor behavior and treatment response. Combination
therapy suppressing GRP78 expression may represent a novel
approach toward eradication of residual tumors. Furthermore, the recent discovery of GRP78 on the cell surface of
cancer cells but not in normal tissues suggests that targeted
therapy against cancer via surface GRP78 may be feasible.
[Cancer Res 2007;67(8):3496–9]
Endoplasmic Reticulum Stress and Cancer
The endoplasmic reticulum (ER) is an essential perinuclear
organelle for the synthesis and folding of secretory and
membrane proteins, which accounts for about one third of the
cell’s proteins. When the protein load exceeds the folding capacity
of the ER, the cells trigger the unfolded protein response (UPR),
which activates the PERK, IRE1/X-box binding protein-1 (XBP-1),
and activating transcription factor-6 (ATF6) signaling pathways as protective measures, resulting in general translational
attenuation, up-regulation of chaperones and folding enzymes,
and enhanced ER-associated degradation of malfolded proteins
(1, 2). Depending on the severity of ER stress, the UPR can result in
cell death through the activation of apoptotic pathways mediated
specifically by the ER, as well as coupling with the mitochondrial pathways (2, 3). ER stress also induces autophagy, a
cellular degradation process implicated in both cell death and
survival (4).
Cancer cells are subject to ER stress because of both intrinsic
and extrinsic factors (5). Cancer cells exhibit elevated glucose
metabolism with increased glycolytic activity, and solid tumors
often grow faster than their blood supply. The latter creates a
tumor microenvironment characterized by glucose deprivation,
acidosis, and severe hypoxia. These combined factors leads to the
accumulation of underglycosylated and misfolded proteins in the
ER, triggering the UPR (Fig. 1). In xenograft models, XBP-1 is
required for survival under hypoxic conditions and tumor growth,
whereas PERK confers advantage for tumor growth (6, 7). Another
major UPR adaptive survival response is the induction of ER
Requests for reprints: Amy S. Lee, Department of Biochemistry & Molecular
Biology and the University of Southern California/Norris Comprehensive Cancer
Center, Keck School of Medicine of the University of Southern California, 1441 Eastlake
Avenue, Los Angeles, CA 90089-9176. Phone: 323-865-0507; Fax: 323-865-0094; E-mail:
[email protected].
I2007 American Association for Cancer Research.
doi:10.1158/0008-5472.CAN-07-0325
Cancer Res 2007; 67: (8). April 15, 2007
chaperone GRP78 in the tumor microenvironment (Fig. 1), which is
the focus of this review.
GRP78 Is a Key Survival Factor in Development and
Cancer
The glucose-regulated protein GRP78, also referred to as BiP
(immunoglobulin heavy-chain binding protein), was discovered in
the late 1970s together with GRP94 and GRP58 as cellular proteins
induced by glucose starvation (1). Residing primarily in the ER,
GRP78 belongs to the HSP70 protein family, which plays critical
roles in the stress of oncogenesis. In addition to facilitating proper
protein folding, preventing intermediates from aggregating, and
targeting misfolded protein for proteasome degradation, GRP78
also binds Ca2+ and serves as an ER stress signaling regulator (1, 8).
In nonstressed cells, GRP78 binds to ER transmembrane sensor
proteins PERK, IRE1, and ATF6 and maintains them in an inactive
form. When unfolded proteins pull GRP78 away from them, these
pathways are activated, sending signals to the nucleus to trigger
the UPR.
GRP78 is induced by physiologic stress that perturbs ER function
and homeostasis, protecting against tissue or organ damage under
pathologic conditions such as neurotoxic stress, myocardial
infarction, and arteriosclerosis (1). During mouse development,
homozygous disruption of the Grp78 allele results in early
embryonic lethality (9). Transcription of Grp78 is detectable as
early as the two-cell stage and is required for both proliferation and
survival for the embryonic inner cell mass, which are precursors of
the pluripotent stem cells. Through synergistic interaction with
cardiac specific transcription factor, Grp78 transcription is strongly
induced in early embryonic heart, which uses glucose as the major
energy source (10).
Although GRP78 expression is maintained at low basal level in
major adult organs such as the brain, lung, and heart, it is strongly
induced in tumors (3, 11). In support of the notion that GRP78 is
more critically needed for the survival of stressed cells such as
cancer, heterozygous GRP78 mice with half of wild-type (WT) GRP78
level are comparable to WT siblings in growth and development.
However, tumor progression was significantly impeded in these mice
as exemplified by a longer latency period, reduced tumor size, and
increased tumor apoptosis.1 This is consistent with earlier studies
that GRP78 conferred lysis resistance to cytotoxic T cells and tumor
necrosis factor a, and that reduction of GRP78 in xenografts
inhibited tumor formation and growth. GRP78 may also be (12)
important for tumor metastasis because it is elevated in metastatic
cancer cell lines, lymph node metastasis, and knockdown of GRP78
inhibits tumor cell invasion in vitro and growth and metastasis in
xenograft models (13, 14). The mechanism whereby GRP78 promotes
growth and metastasis is just emerging. In addition to stress
tolerance mediated by ER lumen GRP78, it has been reported that
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1
A. S. Lee, manuscript in preparation.
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GRP78: Therapeutic and Prognostic Implications
GRP78 is detected on the surface of highly metastatic prostate
cancer cells and may mediate signal transduction pathways that
induce proliferation and invasion (15).
Therapeutic Implications of GRP78 Induction in
Cancer
Although therapeutic agents that target the tumor vasculature
starve the tumors of vital nutrients, it has the unintended
consequence of GRP78 induction. In xenograft models treated with
antivascular and antiangiogenesis agents, GRP78 induction, which
is hypoxia-inducible factor independent, is most intense in the
viable tumor cells bordering necrotic regions created by the therapy
(16). These cells are highly chemoresistant, correlating with GRP78
overexpression and inhibition of apoptosis. How might GRP78
suppress apoptosis? As a molecular chaperone, it prevents the
formation of malfolded proteins. As a Ca2+-binding protein, it
preserves ER calcium homeostasis. Interestingly, whereas the
majority of GRP78 resides in the ER lumen, a fraction of GRP78
exists as an ER transmembrane protein, with its N-amino portion in
the cytosol (17). This could provide an explanation why GRP78 may
be able to directly inhibit the activity of proapoptotic effectors
localized to the ER. For example, GRP78 binds and inhibits the
activation of caspase-7, an executor caspase activated by both ER
stress and genotoxic drugs (5, 17–19). GRP78 also binds and
suppresses the activation of the BH-3 only proapoptotic protein
BIK, its downstream target BAX, and prevents cytochrome c release
from the mitochondria (20, 21). Furthermore, GRP78 in complex
with other ER transmembrane proteins may also indirectly
modulate the activity of these and other proapoptotic components.
Thus, in multiple tumor types including lung, bladder, stomach,
breast, gastric, and epidermoid carcinoma, GRP78 overexpression
confers resistance to a wide variety of chemotherapeutic agents, and
knockdown of GRP78 sensitizes the tumor cells to drug treatment
(5). In malignant glioma, which represents a most malignant and
resistant form of cancer, GRP78 is highly elevated, and knockdown
of GRP78 enhances the efficacy of Temozolomide, the current
standard of care for such cancer.2
GRP78-mediated drug resistance is not limited to proliferating
tumor cells. Knockdown of GRP78 induces strong killing of growtharrested, dormant cancer cells treated with Adriamycin/doxorubicin, a topoisomerase inhibitor, suggesting that dormant cells rely
on GRP78, rather than cell cycle arrest, a commonly held concept,
for drug resistance (20). Similarly, quiescent tumor-associated
endothelial cells also depend on GRP78 for resistance because
knockdown of GRP78 greatly enhances its drug sensitivity.3 These
new findings imply that drugs against GRP78 will be particularly
potent to eradicate residual tumor because they can overcome
drug resistance not only in proliferating cancer cells, but also in
dormant cancer cells, as well as in nontumor cells supporting
tumor growth (Fig. 1).
GRP78 as a Therapeutic Target and Mediator of
Cancer-Specific Therapy
Given the importance of GRP78 in cancer cell survival, it
represents a prime target for anticancer agents. Interestingly, several
2
P. Pyrko, A.H. Schönthal, F.M. Hofman, T.C. Chen, A.S. Lee. The unfolded protein
response regulator GRP78 as a novel target for increasing chemosensitivity in
malignant gliomas, submitted for publication.
3
F.M. Hofman, J. Virrey, D. Dong, et al. GRP78 confers chemoresistance to gliomaassociated brain endothelial cells, submitted for publication.
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naturally occurring compounds with putative anticancer activity
inhibit either GRP78 expression or its activity at pharmacologic
concentrations (Fig. 1). This includes genistein, an active ingredient
of soy, ( )-epigallocatechin gallate (EGCG), a green tea component,
and salicyclic acid from plants (18, 22, 23). Nonetheless, these
compounds act on many cellular targets and pathways in addition
to GRP78. In contrast, the highly lethal bacterial AB5 subtilase
cytoxin specifically cleaves GRP78 at a single amino acid, raising
the interesting idea of exploiting this for anticancer therapy (24).
Furthermore, GRP78 is an intracellular target for the melanoma
differentiation–associated gene-7/interleukin 24 (MDA7/IL-24)
produced by immune cells, which induces cancer-selective growth
suppression and apoptosis in a wide range of human cancers (25).
Screening of compounds from microbes that specifically
suppress the activation of the GRP78 promoter identified versipelostatin, which has no effect on basal GRP78 expression but
inhibits transcriptional activation of the Grp78 gene by glucose
starvation (26). This macrocyclic compound, which also disrupts
some components of the UPR, selectively kills glucose-deprived
cancer cells and acts synergistically with cisplatin in inhibiting
tumor growth in xenografts. These observations, although preliminary and require more work on drug development, provide the
proof of principle that inhibitors of GRP78 can be used in
combination with standard therapeutic agents to enhance drug
efficacy and possibly eliminate residual resistant tumor.
The recent discovery that GRP78 can be found on the cell surface
of tumors but not in normal organs opens up an exciting
opportunity of targeting cell surface GRP78 function as well as
using it as a cancer-targeting marker (Fig. 1). How GRP78 escapes
to the cell surface in tumor cells is not well understood, but it may
involve oversaturation of the ER retention system, cotrafficking
with cell surface client proteins, ER transmembrane GRP78 cycling
to the cell surface, as well as specific mechanisms adapted by
tumor cells. Cell surface GRP78, as a high-affinity receptor for
activated a2-macroglobulin, is postulated to promote proliferation,
survival, and metastasis of prostate cancer cells (15). As proof of
principle that cell surface GRP78 can serve as a conduit for cancerspecific delivery of cytotoxic agents, systemic administration of
synthetic chimeric peptides with GRP78 binding motifs fused to
proapoptotic sequence–suppressed tumor growth without affecting normal tissues (27). Similarly, other GRP78 targeting peptides,
when linked to taxol, induced apoptosis in the targeted cancer cells
(28). Another major advance is that cell surface GRP78 is the
receptor for the angiogenesis inhibitor Kringle 5 (K5) of human
plasminogen (19). Following internalization, K5 blocked the
antiapoptotic activity of GRP78 and induced cell death. Although
the primary target for K5 is likely to be growth-stimulated
endothelial cells supporting tumor progression, recombinant K5
also induced apoptosis in stressed fibrosarcoma cells where surface
GRP78 was also detected (19). Therefore, in principle, this class of
drugs, which are currently tested in clinical trials, should have dual
antiangiogenic and antitumor activities while sparing normal
organs and tissues.
GRP78 as a Novel Biomarker for Tumor Behavior
and Responsiveness to Therapy
In human cancers, elevated GRP78 level generally correlates with
higher pathologic grade, recurrence, and poor patient survival in
breast, liver, prostate, colon, and gastric cancers; however, there are
differing reports on lung cancer and an apparent exception for
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Cancer Research
Figure 1. ER stress induction of GRP78 in the tumor microenvironment. Both intrinsic and extrinsic factors lead to the up-regulation of GRP78 (also referred to as BiP)
and its cell surface expression in tumor cells. Through inhibition of apoptosis, GRP78 facilitates tumor progression, immune resistance, metastasis, and drug
resistance. Dormant tumor cells, as well as quiescent tumor endothelial cells, also rely on GRP78 to escape chemotherapy. Anticancer compounds that either inhibit
the stress induction of GRP78 or suppress its catalytic function have been identified from multiple sources. When used in combination therapy, they should
enhance drug efficacy, lower resistance and assist in eradicating residual tumor. GRP78 has also been identified as a cell surface receptor for Kringle 5 of human
plasminogen and the activated form of the a2-macroglobulin. Because cell surface GRP78 is not detected in normal organs, it can serve as a conduit for cancer-specific
delivery of cytotoxic agents via GRP78 binding peptides. Autoantibody levels against GRP78 in patient serum, as well as expression levels of GRP78 in biopsies,
may represent novel biomarkers in stratifying patients for tumor behavior and responsiveness to treatment. Abbreviations: N, nucleus; ER, endoplasmic reticulum;
C, cytoplasm.
neuroblastoma that requires further investigation (13, 14). Autoantibodies against GRP78 at high levels in prostate cancer patients
have also been reported, associating with aggressive tumor
behavior (29, 30). Furthermore, expression of GRP78 was recently
examined retrospectively in prostate cancer patients during the
development of castration resistance (31). GRP78 is strongly upregulated during the transition from localized prostate cancer to
metastatic castration and may serve as a novel prognostic indicator
of recurrence in untreated patients with localized tumor.
In the management of breast cancer patients, there are at
present only two biomarkers that are used to predict potential
benefits of adjuvant therapy for the disease, hormone receptor
status, and Her2/neu status. The utility of these biomarkers to
eliminate ineffective treatment cannot be underestimated. For
women with hormone receptor–negative tumors, adjuvant hormonal therapy will not reduce the risk of recurrence. Therefore,
such women may be spared the toxicities of such agents. Similarly,
patients whose tumors do not overexpress Her2/neu may be
spared treatment with Herceptin. Unfortunately, similar tests that
would predict benefit from adjuvant systemic chemotherapy
Cancer Res 2007; 67: (8). April 15, 2007
agents do not exist. Such tests would be useful in avoiding the
toxicity associated with chemotherapy in patients who would not
benefit from treatment with these agents. Based on preclinical
studies strongly suggesting that GRP78-positive tumors may be
resistant to topoisomerase inhibitors (5, 16–20), a retrospective
study was conducted to evaluate the value of GRP78 as a
biomarker for treatment response. The study revealed that twothirds of breast cancer patients show moderate to high levels of
GRP78 in biopsies before treatment, and that in patients who
received adjuvant systemic chemotherapy with Adriamycin-based
regimens, GRP78 positivity indicated a higher risk of recurrence
(32). Thus, upon validation, GRP78 positivity might identify
patients who could be spared the toxicities of Adriamycin-based
adjuvant chemotherapy. Another observation that warrants additional investigation is whether GRP78 positivity might also identify
patients who are more likely to benefit from treatment with
Adriamycin followed by taxanes (32). In preclinical studies with
estrogen-positive human breast cancer cells, GRP78 confers
resistance to estrogen starvation–induced apoptosis through
suppressing the activity of BIK (21). Thus, GRP78 level may also
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GRP78: Therapeutic and Prognostic Implications
provide guidance on selection of patients who will benefit from
antiestrogen and aromatase inhibitor therapy. Although it should
be emphasized that most human cancers are relatively heterogeneous diseases and many factors need to be considered when
building models to predict outcome, if our findings on GRP78 are
confirmed, the integration of testing GRP78 expression level into
the management strategies of breast cancer patients would
substantially enhance treatment by reducing exposure to agents
that are not likely to be beneficial to the patient (Fig. 1). This
approach should also be applicable to other forms of cancer.
Concluding Thoughts and Future Directions
Elimination of residual tumor remains a major challenge for
cancer therapy. The recent explosion in new knowledge on GRP78
suggests that it may represent a unifying mechanism for tumor
resistance and a novel predictive biomarker to guide patient
treatment, and this warrants vigorous testing in preclinical and
clinical settings. The exciting recent discoveries also raise new
important questions. How does GRP78 regulate tumor growth as
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well as invasion and metastasis? Does GRP78 also play important
roles in the survival and function of nontumor cells supporting
cancer growth and recurrence? Are there specific adaptive
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Acknowledgments
Received 1/24/2007; revised 2/28/2007; accepted 3/2/2007.
Grant support: National Cancer Institute grants CA027607 and CA111700, the
Susan G. Komen Foundation, and the L.K. Whittier Foundation.
I thank Darcy Spicer, Susan Groshen, Peter Baumeister, Miao Wang, and members
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GRP78 Induction in Cancer: Therapeutic and Prognostic
Implications
Amy S. Lee
Cancer Res 2007;67:3496-3499.
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