MINI REVIEW ARTICLE
published: 11 February 2013
The molecular chaperone GRP78/BiP in the development of
chemoresistance: mechanism and possible treatment
Corinna Roller and Danilo Maddalo*
Institute ofToxicology and Genetics, Karlsruhe Institute ofTechnology, Eggenstein-Leopoldshafen, Germany
Gerald Batist, McGill University,
Marc Poirot, Institut National de la
Santé et de la Recherche Médicale,
Jian Hui Wu, McGill University,
Danilo Maddalo, Institute of
Toxicology and Genetics, Karlsruhe
Institute ofTechnology, Hermann von
Helmholtz Platz 1, 76344
notable progresses in the past decades. However, after an initial response, tumors even-
tually became resistant to chemotherapy.This phenomenon, known as chemoresistance,
accounts for the death of most cancer patients. Several studies in patients refractory to
the cell membrane in malignant but not in benign cells. In this communication we review
studies on the role and the mechanism of action of GRP78/BiP during development of
chemoresistance in cancer cells. In addition we discuss the possible role of GRP78 as a
biomarker and as a target in cancer therapy.
Keywords: cell stress, chaperone, unfolded protein response, drug resistance, therapy
growth is their ability to trigger the stress response. When tumors
become refractory to therapy in the course of treatment with
chemotherapeutic drugs, proteins involved in stress-regulatory
pathways are usually found upregulated. One of these proteins
is the 78-kDa glucose regulated protein GRP78 (also known as
of chaperones and localizes mainly in the endoplasmic reticulum
(ER; Haas and Wabl, 1983; Hendershot et al., 1994; Hendershot,
on one hand it functions as resident chaperone regulating protein
folding and preventing aggregation;on the other hand it regulates
the binding to the ER transmembrane proteins Activating Tran-
scription Factor 6 (ATF6), Inositol REquiring protein 1 (IRE1),
and PKR-like Endoplasmic Reticulum Kinase (PERK; Hender-
shot et al., 1994; Hendershot, 2004). Accumulation of unfolded
peptides titrates GRP78 away from these three “stress sensors”
inducing their activation. Once activated,the UPR can be divided
into two phases: early, pro-survival and late, pro-apoptotic UPR.
Intriguingly it is often observed that genes up- or downstream
the UPR are upregulated in several type of cancers (Ma and Hen-
dershot, 2004) suggesting that chronic activation of this pathway
results in a growth advantage for tumors.
in the cytoplasm and at the cell membrane. Re-location of GRP78
has been associated to development of drug resistance and cell
variant of GRP78/BiP, know as BiPva, lacks the N-terminal ER
localization sequence and that this alternative splicing is specific
to cancer cells (Ni et al., 2009). Considering the role GRP78 plays
is therefore urgent finding compounds inhibiting its pro-survival
GRP78/BiP AS MAIN REGULATOR OF CELL STRESS
GRP78 IN THE ENDOPLASMIC RETICULUM
The ER is a cellular organelle where proteins are folded and/or
modified prior to their export either to the cytoplasm or the cell
exposure of cells to chemicals,lack of nutrients or hypoxia induce
protein aggregation,and misfolding in the ER. GRP78/BiP,as ER-
resident chaperone, has the dual function of regulating protein
ditions on the other hand. In normal conditions,GRP78 is bound
IRE1, and the transcription factor ATF6 (Wang et al., 2009).
Upon accumulation of unfolded proteins within the ER, GRP78
is titrated away from these stress sensors leading to their activa-
tein 1 (Xbp1; Cox et al., 1993). The spliced form of Xbp1 induces
transcription of a specific subset of genes coding for proteins that
play a role in ER-mediated peptide folding. Similarly the tran-
scription factor ATF6 in its GRP78 unbound from translocates
into the Golgi where it is cleaved and activated (Wang et al.,
2000). Activated ATF6 can induce transcription of the molecu-
lar chaperones GRP78 and GRP94 as well as of Xbp1, indicating
a cross-talk between these two arms of the UPR (Yoshida et al.,
2001). The transmembrane kinase PERK homodimerizes, under-
goes autophosphorylation and inhibits the alpha subunit of the
February 2013 | Volume 4 | Article 10 | 1
Roller and Maddalo GRP78 in chemoresistant cancers
eukaryotic initiation factor 2 (eIF2α). As a result de novo protein
synthesis is blocked preventing novel polypeptides from accumu-
lating in the ER lumen (Koumenis et al., 2002). However, pro-
longed eIF2α phosphorylation leads to the activation of the tran-
(Scheuner et al., 2001). ATF4 induces the transcription factor
CHOP/GADD134 (Fawcett et al., 1999) that in turn induces the
pro-apoptotic protein Bax (Yamaguchi and Wang, 2004) and Bim
(Puthalakath et al., 2007) and inhibits the anti-apoptotic protein
Bcl-2 (McCullough et al., 2001). Based on the time of activation,
the UPR has opposite effects on cell fate: while at the early stage
it induces cell survival and increases refolding activity within the
ER by activating ATF6 and IRE1 branches, at later time points
results in cell death induction by activating the PERK-eIF2-ATF4
axis (Figure 1).
GRP78 OUTSIDE THE ENDOPLASMIC RETICULUM: THE RIGHT BALANCE
Immunohistochemical as well as genome wide analysis on patient
refractory to therapy like glioma (Pyrko et al., 2007), leukemia
(Uckun et al., 2011), prostate (Daneshmand et al., 2007), and
to be the key feature for cancer cells that chronically upregulate
the UPR without however inducing apoptosis. The observation
benign cells indicates that the extra-ER function of this protein is
crucial for its pro-survival action. Even if it is not clear yet how
UPR pro-survival branch and the receptor-mediated activation of
the Akt/PI3K pathway. Alternatively the pro-apoptotic action of
FIGURE 1 | BiP as master regulator of the Unfolded Protein Response.
Upon accumulation of unfolded peptides in the Endoplasmic Reticulum (ER)
the chaperone BiP is titrated away from the stress sensors PKR-like ER
kinase (PERK), inositol-requiring protein 1 (IRE1) and activating transcription
factor 6 (ATF6). When released by BiP , PERK homodimerizes and
autophosphorylates before phosphorylating the alpha subunit of the
eukaryotic initiation factor 2 (eIF2α). eIF2α phosphorylation inhibits
transcription while activating the transcription factor ATF4 and its target
gene C/EBP homologous protein (CHOP). CHOP induces apoptosis by
suppressing Bcl-2 and activating Bim and Bax gene expression. Similarly to
PERK, the kinase/endonuclease IRE1 homodimerizes and
autophosphorylates before splicing Xbp1 mRNA (Xbp1u: Xbp1 unspliced;
Xbp1s: Xbp1 spliced).The third branch of the UPR is activated after cleavage
of the transcription factor ATF6 in the Golgi (cATF6). Both cATF6 and Xbp1s
regulate transcription of pro-survival genes like Glucose Regulated Proteins
78 and 94 (GRP78 and 94) and Protein Disulfide Isomerases (PDIs). In
addition to its canonical function in the ER, it has also been shown that BiP
can localize to the plasma membrane and regulate the Akt/PI3K pathway.
(Yellow dots indicate phosphorylation. For simplicity PERK and IRE1 are
shown as monomers).
Frontiers in Pharmacology | Pharmacology of Anti-Cancer Drugs
February 2013 | Volume 4 | Article 10 | 2
Roller and MaddaloGRP78 in chemoresistant cancers
the UPR could be compensated by the activation of the Akt/PI3K
pathway, resulting in cell survival.
Since the UPR is frequently upregulated in refractory tumors
and GRP78 plays a crucial role in its activation, it is expected that
cancers with higher GRP78 levels will respond less to chemother-
biomarker to predict patient response to therapy on one hand
and a good target to overcame acquired resistance on the other
GRP78/BiP AS BIOMARKER IN CHEMORESISTANT TUMORS
One of the characteristic features of cancer cells is their ability
to develop resistance to chemotherapeutic agents. This property
translates into an initial response of the patients to therapy. How-
ever within a period that can vary from some months to years
cancer grows back and is unresponsive to the initial therapy.
GRP78/BiP has been found overexpressed both at the gene and at
the protein level at this stage. For example GRP78 is found com-
monly overexpressed in breastcancer lesions refractory to therapy
(Gazit et al., 1999; Fernandez et al., 2000). Treatment of human
breast cancer cells MDA-MB-435 with anti-angiogenic factor
Combretastatin A4P showed increased expression of GRP78/BiP
in the surviving cells, indicating that higher GRP78 levels corre-
late to higher resistance (Dong et al., 2005). In addition GRP78
increased expression has been observed in a panel of MCF-7
pared to the parental line (Wosikowski et al., 1997). Intriguingly
it has been shown that while high GRP78 levels are predictive of a
treated with the topoisomerase inhibitor doxorubicin (Lee et al.,
2006; Scriven et al., 2009), in patients treated sequentially with
doxorubicin and taxanes GRP78 is positively associated with bet-
ter outcome (Lee et al., 2011). These observations indicate that
in breast cancer.
In addition it has been shown that GRP78 induces chemore-
sistance development in brain endothelial cells, favoring there-
fore tumor vascularization and metastatic spread (Virrey et al.,
2008) and that GRP78 inhibition re-sensitize acute lymphoblastic
has also been found to contribute to castration resistant prostate
cancer (CRPC) development (Tan et al., 2011). Immunohisto-
chemical analysis has shown that GRP78 levels are overexpressed
Even if no clear mechanism of action has been described, it has
been showed that knockout of GRP78 blocks Akt-PI3K pathway,
resulting in tumor growth inhibition (Fu et al., 2008).
TARGETING GRP78/BiP IN REFRACTORY CANCERS
Since GRP78/BiP is overexpressed in malignant cells resistant
to therapy, it is a valid target to overcame chemoresistance. An
vation that it translocates on the plasma membrane of malignant
but not benign cells, offering the possibility of cancer specific
drug delivery with functionalized nanoparticles. Table 1 shows
a summary of the compounds described in the following section.
Table 1 | List of GRP78 inhibitors.
Subtilase toxin AB5
de Ridder et al. (2012)
Misra and Pizzo (2010)
Brändlein et al. (2007)
Ermakova et al. (2006)
Paton et al. (2006)
Matsuo et al. (2009)
Umeda et al. (2005)
Maddalo et al. (2012)
Cunningham et al. (2005), Gupta et al. (2006)
Yoneda et al. (2008)
Arap et al. (2004)
Passarella et al. (2010)
The drugs designed to target GRP78/BiP can be divided into
three major categories: (1) Antibodies, (2) Natural compounds,
Specific antibodies targeting GRP78 either in the ER or on the
cell surface have successfully demonstrated reduction in tumor
growth and proliferation. The mouse monoclonal antibody C38
recognizes the C-terminal domain of the murine GRP78 exposed
on the cell membrane inhibiting PI3K/Akt proliferative pathway
in melanoma cells (de Ridder et al., 2012). A similar mecha-
nism of action has been demonstrated for the antibody C107
in a melanoma mouse model (de Ridder et al., 2012). The anti-
CDT GRP78 antibody binds the cell expressed GRP78 in human
prostate cancer cells significantly reducing tumor growth (Misra
and Pizzo, 2010). Treatment of several prostate cancer cell lines
with this antibody showed increased p53 protein levels as well
as induction of the pro-apoptotic proteins Bad, Bax, and Bak.
Another antibody, SAM-6 (Brändlein et al., 2007), binds to an O-
glycosylatedformof GRP78expressedonthecellsurfaceof cancer
cells but its anti-growth effect has not been tested yet (Rauschert
et al., 2008).
The green tea extract (−)-epigallocatechingallate (EGCG) binds
the ATPase domain of GRP78 inhibiting its catalytic activity. In
function of the chaperone. Administration of EGCG has shown
re-gain of sensitivity to the topoisomerase inhibitor etoposide in
breast cancer cells (Ermakova et al., 2006). Moreover it has been
age, like Subtilase AB5 derived from E. coli (Paton et al., 2006), or
reducing its expression levels like Versipelostatin (derived from
Streptomyces versipellis; Matsuo et al., 2009) or Prunustatin A,
February 2013 | Volume 4 | Article 10 | 3
Roller and Maddalo GRP78 in chemoresistant cancers
a compound isolated from Streptomyces violaceusniger (Umeda
et al., 2005).
Peptides binding GRP78 are employed either for direct inhibition
of GRP78 activity or to coat nanoparticles to deliver cytotoxic
One of the direct inhibitors of GRP78 is the Bag-1 peptide,
derived from a novel interaction site on the co-chaperone Bag-1
1 peptide ectopic expression in several malignant but not benign
prostate cancer cell lines as well as in prostate cancer xenograft
models reduces tumor growth by inhibiting GRP78 refolding
activity and inducing CHOP-mediated apoptosis. Similarly the
M4 peptide was derived from the Mda-7 tumor suppressor pro-
tein after the observation that Mda-7 intratumoral gene transfer
was able to reduce growth of several cancers (Cunningham et al.,
2005; Gupta et al., 2006).
The evidence that GRP78 is selectively expressed on the sur-
face of several cancer types gives the possibility of exploiting
molecules that can bind GRP78 for selective drug delivery. A
good example is given by the cyclic peptide Pep42 (CTVALPG-
GYVRVC) that can bind selectively to surface GRP78 and can
function as cell penetrating peptide (Yoneda et al.,2008).Also the
peptides WIFPWIQL and WDLAWMFRLPVG are able to bind
GRP78 on the cell surface and have been employed successfully
in in vivo models of prostate and breast cancer for the delivery of
a cell death-inducing peptide (Arap et al., 2004). GRP78-binding
peptides can be used also in conjugation to other carriers like
liposomes or nanoparticles. In fact the peptide WIFPWIQL has
been used conjugated to liposomes for doxorubicin delivery to
cancer endothelial cells and in an in vivo colon carcinoma mouse
model (Katanasaka et al., 2010). Similarly the peptide GIRLRG
was employed for coating nanoparticles containing placitaxel in
irradiated breast carcinomas and showed increased cell death
compared to known chemotherapy approaches (Passarella et al.,
CONCLUSION AND PERSPECTIVES
The role of GRP78 in development of chemoresistance is just
emerging. The increasing availability of genome wide and array
data shows that GRP78 is often overexpressed in several types of
not only be a good biomarker to predict response to therapy but
also an appealing target for a more selective chemotherapy.
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Conflict of Interest Statement: The
authors declare that the research was
conducted in the absence of any com-
mercial or financial relationships that
could be construed as a potential con-
flict of interest.
21 January 2013; published online: 11
The molecular chaperone GRP78/BiP
in the development
tance: mechanism and possible treat-
ment. Front. Pharmacol. 4:10. doi:
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