Linking the immunophilin FKBP5 to taxol resistance in ovarian cancer

Cancer Cell & Microenvironment 2015; 2: e692. doi: 10.14800/ccm.692; © 2015 by Shang-Lang Huang, et al.
http://www.smartscitech.com/index.php/ccm
RESEARCH HIGHLIGHT
Linking the immunophilin FKBP5 to taxol resistance in ovarian
cancer
Shang-Lang Huang1, Chuck C.-K. Chao1,2
1
Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic
of China;
2
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China
Correspondence: Chuck C.-K. Chao
E-mail: cckchao@mail.cgu.edu.tw
Received: March 04, 2015
Published online: March 22, 2015
Taxol is a chemotherapeutic drug used to treat a number of cancers, including ovarian and breast cancers.
However, taxol resistance limits treatment efficacy in cancer patients. To study the molecular mechanism of
chemoresistance in ovarian cancer, we established taxol-resistant cells derived from the SKOV3 ovarian
carcinoma cell lineage. Transcriptomic analysis identified 112 highly up-regulated genes in taxol-resistant cells.
Among them, FK506-binding protein 5 (FKBP5) was transiently up-regulated 100 fold in taxol-resistant cells but
showed reduced expression following prolonged culture. FKBP5 silencing sensitized taxol-resistant cells to taxol,
while overexpression of FKBP5 increased resistance to the drug. We observed that several of the newly
identified taxol resistance genes were trancriptionally regulated by FKBP5, and silencing of these genes
sensitized cells to taxol. Our experiments also revealed that FKBP5 forms a protein complex with the androgen
receptor (AR), and this complex regulates the transcriptional activity of both proteins. In addition, we observed
that the Akt kinase pathway is regulated by FKBP5. These results indicate that the FKBP5/AR complex may
affect cancer cell sensitivity to taxol by regulating expression of taxol resistance genes. Our results suggest that
taxol should not be used against ovarian cancer when the Akt/FKBP5/AR axis is activated.
Keywords: Akt; androgen receptor; immunophillin; FKBP5; taxol resistance
To cite this article: Shang-Lang Huang, et al. Linking the immunophilin FKBP5 to taxol resistance in ovarian cancer. Can
Cell Microenviron 2015; 2: e692. doi: 10.14800/ccm.692.
Ovarian cancer is a common gynecological cancer in
developed countries. The introduction of platinum
compounds was an important step for the treatment of this
malignancy. The combination of taxol and common
chemotherapy was shown to improve the treatment of
advanced epithelial ovarian cancer [1]. Nonetheless, a large
fraction of patients show minimal improvements following
this treatment, and the patients who benefit from this therapy
may eventually relapse. The molecular mechanism
underlying chemotherapeutic drug resistance is not fully
understood, especially for taxol resistance. In a recent study,
we used taxol-resistant ovarian cancer cell lines derived from
the SKOV3 cell lineage to identify and characterize novel
targets and kinase signaling pathways involved in taxol
resistance.
Taxol and ovarian cancer
Taxol is a chemotherapeutic drug used to treat a number of
cancers, including ovarian and breast cancers. Taxol and
docetaxel are part of the taxane family of drugs. Taxol
stabilizes microtubules and prevent their disassembly,
therefore producing abnormalities in mitotic spindle
formation, chromosome segregation, and cellular division.
Drug resistance has been a major obstacle in cancer therapy,
and numerous clinical studies have revealed that multidrug
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resistance may be involved in the death of more than 90% of
cancer patients. Previous studies on the mechanisms of taxol
resistance have identified various factors involved in this
process, including tubulin mutations, tubulin isoforms,
overexpression of multidrug resistance proteins, and Bcl-2
activity. The inhibitor of Bcl-2/Bcl-XL termed ABT-737 was
shown to be highly efficient at enhancing sensitivity of taxol
[10]
. In addition, the dual Bcl-2/Mcl-1 inhibitor S1 efficiently
synergized with taxol by enhancing apoptosis and taxol
sensitization in chronic myelogenous leukemia [11]. However,
identification of single factors involved in taxol
chemoresistance, such as Tau, Bcl-2 and Mcl-1, might not be
sufficient to fully explain the drug-resistant phenotype of
cancer cells detected in human patients [6,7].
The PI3K/Akt signaling pathway is crucial for cancer
proliferation
The PI3K/Akt cellular pathway is critical for cell survival,
proliferation, and angiogenesis, and is frequently
dysregulated in human cancer [12]. Accordingly, inhibition of
the PI3K/Akt pathway using the PI3K inhibitors wortmannin
and LY294002 inhibits cancer cell proliferation [13]. There are
three major classes of PI3Ks but only class I has been
heavily implicated in oncogenesis [14]. Akt is activated by
PI3K, and subsequently modulates several critical substrates
(such as AR, NF-κB, FOXO transcription factors,
Bcl-2-associated agonists of cell death, GSK3β and MDM2),
which regulate cell survival, cell cycle progression, and
expression of the multidrug resistant protein ABCB1/P-gp
[14-16]
. On the other hand, taxol-resistant (txr) cells established
in our lab also showed enhanced Akt phosphorylation (except
when ABCB1 was overexpressed). It was therefore proposed
that activation of the PI3K/Akt pathway may represent an
obstacle to anticancer drug treatments. Accordingly,
inactivating the PI3K/Akt pathway using LY294002
sensitized taxol-resistant DU145 prostate cancer cells to
taxol, possibly due to the high PI3K/Akt activity observed in
these cancer cells [31]. Therefore, PI3K/Akt inhibitors could
be helpful to circumvent chemoresistance, even in
combination with other anticancer therapies.
Several PI3K/Akt inhibitors have been designed and
investigated in clinical trials. For example, inhibition of PI3K
activity using LY294002 was shown to sensitize U251
glioblastoma cell line cells to radiation [17]. Furthermore,
enhanced taxol sensitivity was achieved with the Akt
inhibitor MK-2206 in the SKOV3 ovarian cancer cell line [18].
In addition to the efficient inhibition produced by the Akt
inhibitor on SKOV3 epithelial carcinoma, several PI3K/Akt
inhibitors have shown potent antitumor activity in squamous
cell lung carcinoma [12,19].
FKBP5 hyperactivity in taxol resistance
FK506 binding protein 5 (FKBP5) represents a protein of
the immunophilin family and is also a peptidyl-prolyl
cis/trans isomerase (PPIases) involved in rotating peptide
bonds directly from the cis conformation to trans. For this
reason, the co-chaperone FKBP5 plays an important role in
protein folding and transportation. One of the major
functions of FKBP5 is to modulate steroid receptor activity
(e.g., receptors for progesterone, androgens and
glucocorticoids) by interacting with heat shock proteins (e.g.,
Hsp90/Hsp70) [24,25].
Recent studies on the role of FKBP5 in regulating
apoptosis showed that FKBP5 silencing overcomes
resistance to apoptosis in acute lymphoblastic leukemia [26],
melanoma [28], and glioma [30]. Furthermore, FKBP5
promotes
activation
of
genes
responsible
for
epithelial-to-mesenchymal transition (EMT), and it also
improves migration and invasion of melanoma cells [29]. In
addition to protein trafficking, FKBP5 is also involved in
regulating
Akt
activity.
FKBP5
can
facilitate
PHLPP-mediated dephosphorylation of AktS473, inhibiting
Akt activity in pancreatic cells. Therefore, FKPB5
knockdown reduced PHLPP levels and upregulated Akt
phosphorylation [27,37]. However, the levels of AktS473
phosphorylation were not enhanced by FKBP51
downregulation in normal and cancerous tissues of mice
transplanted with a melanoma xenograft [35]. Besides, FKBP5
positively regulates Akt activity in SKOV3 cells as seen by
the observations that ectopic expression of FKBP5 resulted
in elevated AktS473 phosphorylation, whereas FKBP5
silencing decreased S473 phosphorylation [15]. Therefore, the
possibility that FKBP51 deactivates Akt may depend on
specific cell types or pathways upregulated in tumors.
Apart from binding and regulating Akt, FKBP5 also
interacts with the acetyltransferase P300, a transcriptional
co-activator [29]. This observation suggests that FKBP5 may
act as a histone chaperone, and may be involved in
transcriptional regulation.
In our study, FKBP5 was not only overexpressed in
taxol-resistant ovarian SKOV3 cells, but ectopic expression
of FKBP5 also enhanced chemoresistance in SKOV3 cells
(by 8.7 fold for taxol and 1.8 fold for vincristine). Conversely,
depleting FKBP5 using short-hairpin RNA induced taxol
sensitivity in a resistant SKOV3 cell subtype (i.e.,
SKOV3/Tx600, 8.9 fold). Although the manner in which
FKBP5 is involved in regulating drug sensitivity remains
unclear, it appears to represent a crucial factor in determining
sensitivity to mitotoxic drugs in ovarian cancer cells. In
addition, several studies indicate that FKBP51 may represent
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an interesting target for the treatment of various cancers
[32-34]
.
The androgen receptor potentiates FKBP5 activity in taxol
resistance
Besides possessing PPIase and steroid receptor
co-chaperone activities, FKBP5 is regulated by the androgen
receptor (AR). This receptor is part of the steroid hormone
receptor family, and contains a DNA-binding domain and a
hormone-binding domain. The AR is activated by binding
androgens in the cytoplasm, which leads to its translocation
to the nucleus, where it regulates the transcription of various
genes, including prostate-specific antigen (PSA). AR
signaling is known to regulate the growth and development
of prostate and breast cancer cells [20,21]. The PI3K inhibitor
LY294002 inhibits AR activity through phosphorylation and
inactivation of GSK3β, a downstream substrate of PI3K/Akt,
which results in nuclear accumulation of β-catenin. β-catenin
then interacts with the AR to induce HER3 gene expression
and cell proliferation, an observation which shows the
importance of the association between AR and Wnt signaling
pathways in driving of cancer cell growth [21]. Functional
annotation of AR co-expressed genes showed involvement of
this protein in cell cycle or cellular metabolism, including
regulation of mitosis and mitotic metaphase/anaphase
transition, glucose metabolism, and oxygen homeostasis [23].
Our preliminary results identified novel upregulated
taxol-resistant (txr) genes that were positively associated
with the AR and FKBP5. The AR and FKBP5 both produced
positive regulation in drug resistance suggesting contribution
of both proteins in this process. Pathway enrichment analysis
of AR-related txr genes showed that the txr genes identified
were involved in regulation of the cell cycle (H1F0),
development (LCN2, SPP1, FGFR2), cellular transport
(ABCB1), and immune responses (LCN2). Other studies
reported that taxol therapy affects AR activity, but
establishing the exact mechanisms involved in this process
awaits further studies.
ABC transporters and taxol resistance
Multidrug resistance (MDR) represents an obstacle to
cancer therapy, and is constantly associated with
chemotherapy-based treatment failure. ABCB1/P-gp, a drug
efflux pump, is one of the main target leading to taxol
resistance [2]. Accordingly, P-gp overexpression is involved
in the MDR phenotype which has been detected in various
types of cancer cells. Moreover, P-gp expression can also be
used to grade the pathological level of colorectal carcinoma
cases, with high values being found in well differentiated
tumors and low values being observed in poorly
differentiated tumors [5]. A meta-analysis indicated that P-gp
may not be useful to predict cancer outcome. On the other
hand, elevated P-gp expression correlates with poor survival
in epithelial ovarian cancer [3,4].
In our microarray analysis of taxol-resistant SKOV3 cells,
several ABC efflux transporters were overexpressed more
than 2 fold compared to parental cells (i.e., ABCB1, ABCG2,
ABCB6, and ABCC2). Up to now, at least 48 ABC
transporters have been described and classified into seven
subfamilies in humans (from ABCA to ABCG) [8]. The
transporters ABCB1, ABCG2, and ABCCs appear to
represent the main receptors involved in MDR-cancer cells [9].
Transcriptomic profiling revealed that ABCB1 remains a
major target to reduce taxol resistance [15]. To improve cancer
treatment, pharmacological inhibitors of the transporter
pathways described here have been studied. However,
targeting the ABC transporters has produced mixed results so
far due to high toxicity [22].
Linking FKBP5/AR to taxol resistance
We recently found that the immunophilin FKBP5 is
transiently overexpressed in an ovarian cell line selected for
taxol resistance. Functional analysis indicated that FKBP5
expression level can be enhanced by the AR, and that this is
critical for upregulating a sub-set of genes important for
taxol resistance (e.g., ABCB1) [15]. This is the first
observation, to our knowledge, that the immunophilin
FKBP5 is linked to cell response to taxol, at least in ovarian
cancer cells. Since ABCB1 has been shown to represent an
important factor for multiple drug resistance [36], the finding
that the FKBP5/AR/ABCB1 axis plays a role in taxol
resistance in ovarian cancer cells supports the usefulness of
our strategy. Although our findings are different from those
of Pei et al. who observed that FKBP5 reduces pAkt levels
[37]
, they are consistent with the findings of Fabian et al. [38]
who used mutational and pharmacological studies to show
that FKBP inhibitors may not inhibit the Akt-FKBP-PHLPP
pathway. Additional proteins that interact with FKBP5 may
provide an additional layer of regulation, and this regulation
is likely to be cell-type dependent. Our findings suggest that
regulation of taxol resistance genes by FKBP5 is specific to
the drug used. Identification of unique taxol resistance genes
may provide important markers for the development of new
cancer treatments based on single or multiple drug(s).
Taken together, our results confirm that FKBP5 acts as a
scaffold protein [39] that recruits the AR and regulates gene
expression. Amplification of FKBP5 expression also
subsequently upregulates target taxol resistance genes such
as ABCB1, H1F0, BMP5, and FGFR. However, our current
data did not show whether FKBP5 can directly regulate taxol
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While the mechanism of action of transporters (e.g.,
ABCB1) involved in drug resistance is well known, targeting
of these transporters has failed due to high toxicity [22]. To
identify drugs for second-line chemotherapy and prevent
chemoresistance, it is imperative to determine the
mechanisms underlying this process. Transcriptomic analysis
of txr cells has identified alternative drug targets to improve
treatment efficacy. The finding of novel txr genes whose
expression is controlled by FKBP5 appears to be an
important step in this direction.
Acknowledgements
This work was supported by grants (to C.C.-K.C) from the
Ministry of Science and Technology of Taiwan (Contract No.
NSC100-2320-B-182-026-MY3
and
MOST103-2320B-182-031) and Chang Gung University and Chang Gung
Memorial Hospital (Contract No. CMRPD1C0191 and
CMRPD190053). We apologize to colleagues whose work
was not cited due to space constraints.
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