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ONCOLOGY LETTERS 15: 41-47, 2018
Abstract. Drug resistance is a primary cause of chemo-
therapeutic failure; however, how this resistance develops is
complex. A comprehensive understanding of chemotherapeutic
resistance mechanisms may aid in identifying more effective
drugs and improve the survival rates of patients with cancer.
Insulin-like growth factor 1 receptor (IGF1R), a member of
the insulin receptor family, has been extensively assessed for
biological activity, and its putative contribution to tumor cell
development and progression. Furthermore, researchers have
attended to drugs that target IGF1R since IGF1R functions
as a membrane receptor. However, how IGF1R participates in
chemotherapeutic resistance remains unclear. Therefore, the
present study described the IGF1R gene and its associated
signaling pathways, and offered details of IGF1R-induced tumor
chemoresistance associated with promoting cell proliferation,
inhibition of apoptosis, regulation of ATP-binding cassette
transporter proteins and interactions with the extracellular
matrix. The present study offered additional explanations for
tumor chemotherapy resistance and provided a theoretical
basis of IGF1R and its downstream pathways for future
possible chemotherapy treatment options.
Contents
1. Introduction
2. IGF1R signaling pathway
3. IGF1R and chemotherapy resistance
4. Conclusions
1. Introduction
Insulin-like growth factor 1 receptor (IGF1R) signaling is
a complicated and regulated network essential for cells to
proliferate and survive. The IGF-IGF1R axis consists of three
receptor tyrosine kinases: IGF1R, insulin-like growth factor-2
receptor (IGF2R) and insulin receptor (INSR). The ligands for
these receptors are insulin, insulin-like growth factor-1 (IGF-1),
insulin-like growth factor-2 (IGF-2) and serum insulin-like
growth factor binding proteins (IGFBPs) (1). IGF-1 and IGF-2
possess autocrine, paracrine and endocrine functions, and
activate IGF1R signaling (2). These growth factors and their
receptors are commonly overexpressed in malignant tumors;
this overexpression may be used to assess cancer through
sustained proliferative signals, anti-apoptotic events, invasion,
metastasis and drug resistance in cancer cells (3).
IGF1R expression and activity increases in numerous
tumor types, including ovarian cancer and rhabdomyosar-
coma, and is reported to contribute to cancer cell proliferation
and apoptosis (4,5). Since IGF1R functions as a membrane
receptor, drugs, including IGF1R tyrosine kinase inhibi-
tors, monoclonal antibodies against IGF1R and monoclonal
antibodies against IGF1R ligands targeting this receptor, are
of particular interest (6). Recently, the function of IGF1R in
chemotherapeutic resistance has gained increasing attention,
and relevant mechanisms of inducing resistance in cancer cells
include overexpressing multi-drug-resistant proteins, dysregu-
lating cell survival and death and interacting with the tumor
microenvironment (7).
2. IGF1R signaling pathway
IGF1R structure and function. IGF1R is an insulin receptor
family member, and a disulde‑linked heterotetrameric trans-
membrane glycoprotein (αββα) that contains an extracellular
ligand-binding domain and an intracellular tyrosine kinase
domain (8,9). The ligand‑binding specicity determinant is
reected in the amino‑terminal cysteine‑rich domain of the
extracellular α subunit, primarily recognizing and binding to
IGF-1 and IGF-2. The intracellular signal transduction depends
on the tyrosine kinase activity the ligand in the transmem-
brane β subunit triggers, permitting specic insulin receptor
substrates (IRS-1 to -4) and Src-homology collagen (Shc)
to phosphorylate, activating downstream mitogen-activated
Function of insulin‑like growth factor 1 receptor in
cancer resistance to chemotherapy (Review)
JINGSHENG YUAN, ZHIJIE YIN, KAIXIONG TAO, GUOBING WANG and JINBO GAO
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Received May 30, 2017; Accepted September 28, 2017
DOI: 10.3892/ol.2017.7276
Correspondence to: Professor Jinbo Gao, Department of
Gastrointestinal Surgery, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology, 1277 Jiefang
Avenue, Wuhan, Hubei 430022, P.R. China
E-mail: jgao@hust.edu.cn
Key wo rds: insulin-like growth factor 1 receptor, cancer,
chemotherapeutic resistance, mechanisms, review
YUA N et al: IGF1R AND CHEMOTHERAPEUTIC RESISTANCE
42
protein kinase (MAPK) and phosphatidylinositol 3-kinase
(PI3K)/protein kinase B (AKT) signaling pathways (6). The
specicity of IGF1R in vivo depends on tissue distribution,
ligand‑binding specicity and receptor differences in intrinsic
signaling (10).
IGF1R is often expressed in normal tissues, serving
multiple physiological functions in growth, development
and feeding (11). The importance of IGF1R in prenatal and
postnatal growth has been demonstrated using knockout
mice (8). In muscle and bone tissues, IGF1R signaling
promotes PI3K/AKT-mediated differentiation and extracel-
lular signal-regulated kinase (ERK) (12). IGF1R also aids in
the maintenance of the myocardium and brain (13).
Cardiac-specific IGF1R signaling promotes protective
physiological hypertrophy, preserving left ventricular function
and inhibiting pathological left ventricular remodeling (14).
Furthermore, IGF1R contributes to glucose metabolism and
neutrophil physiology (15), and is associated with the occur-
rence and development of cardiovascular disease, diabetes and
inammation (16,17).
IGF1R is commonly overexpressed in cancer (18). The
IGF1R signal promotes non-cancerous cells to malignantly
transform (19), and possesses anti-apoptotic and mitogenic
activity (20-22). In addition, IGF1R contributes to invasion,
metastasis and angiogenesis of cancer (23-25). Excessively
activating IGF1R promotes tumors to progress by increasing
glycolysis and biomass production (26), and decreases tumor
sensitivity to hypoxia, low pH and low glucose environ-
ments (27). In addition, expressing IGF1R increases the rate at
which tumor cells proliferate and decreases the rate at which
they are destroyed (28).
IGF1R gene regulation. The 5'‑anking region promoter of
IGF1R is enriched in GC, and lacks the effective transcription
initiation of the majority of eukaryotic genes usually requiring
TATA and CCAAT boxes. This characteristic results in a
partial difference in its gene regulation compared with other
promoter regions (29,30).
IGF1R gene expression is regulated transcriptionally and
post‑transcriptionally. Previous studies have suggested that
numerous transcription factors regulate the IGF1R gene.
Transactivation factors include zinc nger protein specicity
protein 1 (Sp1), forkhead box protein O3 (Foxo3), E2F1 tran-
scription factor, Krüppel-like factor 6, EWS RNA binding
protein 1-Wilms tumor 1 (WT1) fusion protein and high
mobility group A1, all of which bind directly to the IGF1R
promoter (31-34). In contrast, estrogen, BRCA1 DNA repair
associated (BRCA1) and von Hippel-Lindau tumor suppressor
inhibit IGF1R expression by binding to Sp1 (31,35). A previous
study confirmed that WT1 specifically binds to co-WT1
cis‑elements in the IGF1R proximal promoter region, and
decreases IGF1R gene transcription and translation (36).
Overexpressing MYB proto-oncogene transcription factor in
tumor cells increases the expression of IGF-1 and IGF1R by
increasing transcriptional activity (37).
IGF1R‑associated signaling pathways. IGF1R is associated
with multiple signaling pathways via downstream proteins,
including IRS and PI3K (38-40). IGF1R, which mediates
apoptosis-inhibiting signals, and enhances cell metabolism and
protein synthesis via downstream mechanistic ta rget of rapamycin
(MTOR) kinase signaling, activates the PI3K/AKT signaling
pathway (41-43). IGF1R activates the growth factor receptor
bound protein 2 (Grb2)/RAS/RAF/MAPK signaling pathway
to transduce cell growth and proliferation signals (44,45).
IGF1R activation or overexpression is associated with invasion
and metastasis of cancer cells, processes mediated by numerous
signal transduction proteins that affect invasiveness (24,25).
For example, phosphorylating IRS-1 affects the interactions
between epithelial cadherin and β-catenin, and the crosstalk
between the IGF axis and integrins (46). A previous study
demonstrated that protein tyrosine kinase 6 forms a complex
with IGF1R and the adaptor protein IRS-1, which modulates
anchorage-independent growth via the regulation of IGF1R
expression and phosphorylation (23).
Previously, crosstalk between IGF1R and other signaling
pathways has been assessed, with studies focusing on interac-
tions between IGF1R, steroid hormones and other receptor
tyrosine kinases (RTKs) (47). The crosstalk between IGF1R
and focal adhesion kinase (FAK) signaling pathways (38),
IGF1R and the classical Wnt signaling pathways (48,49), and
IGF1R and transforming growth factor β (TGFβ) signaling
pathways have also been further claried (50). In addition,
certain IGF1R signals have been newly identified, namely
RTK heterodimers, including the INSR hybrid receptor, and
IGF1R/INSR that function as dependent receptors intervening
in IGF1R signaling and its regulation (51).
The IGF1R signaling pathway is regulated at multiple
levels; the expression of IGF-2, the presence of IGF2R and
high‑afnity IGFBPs affects ligand‑binding activity (52). In
addition, other extracellular factors, including dendritic cells
and integrins, may contribute to regulating IGF1R activity (53).
Within cells, Notch and apoptosis inducing factor-1 regulates
IGF1R kinase activity (54). Downstream, multiple IGF1R
effectors participate in IRS/PI3K/AKT signal transmission,
including MTOR complex 1, phosphatase and tensin homolog
phosphohydrolase, ribosomal protein S6 kinases, ERK and
c-Jun N-terminal kinase (5,55,56).
3. IGF1R and chemotherapy resistance
Overexpression of IGF1R is associated with poorer chemo-
therapy outcomes for patients with gastric cancer compared
with those with low expression of IGF1R (57). Patients with
co-expression of IGF1R and multi-drug resistance-associated
protein 1 (MRP1) have demonstrated a poorer response with
adjuvant FOLFOX-4 chemotherapy (58). In patients with
human epidermal growth factor receptor 2-negative breast
cancer, the decreased expression of IGF1R was correlated
with an improved response to chemotherapy (59). Blocking
IGF1R signaling facilitates treating bladder cancer cells that
are insensitive to chemotherapy (60). Similar phenomena
have been reported for prostate and ovarian cancer when
IGF1R signaling is blocked (61,62). Although the function
of IGF1R in chemotherapy resistance has been conrmed,
the mechanism remains to be fully elucidated. The present
study assessed IGF1R-associated tolerance mechanisms from
multiple aspects, including promoting proliferation, inhibiting
apoptosis, and inducing changes to ATP-binding cassette
ONCOLOGY LETTERS 15: 41-47, 2018 43
(ABC) transporter proteins and the extracellular matrix
(ECM) (Fig. 1).
Promoting proliferation. A characteristic of tumor cells,
persistent proliferation may be acquired in multiple ways (3).
As chemotherapeutic resistance develops, certain signals
elevate receptor proteins on tumor cell surfaces and permit
cells to avoid growth signal control (57). Changing the recep-
tor's molecular structure, which alters ligand restriction and
promotes the downstream signal to activate, may achieve the
same effect (63).
The Grb2/RAS/RAF/MAPK cascades serve crucial func-
tions in cell proliferation and survival and are aberrantly
activated in drug-tolerant cells. Numerous mechanisms
increase IGF1R expression and activate IGF1R, thereby
promoting signaling cascades and proliferation (64). WT1 is
reportedly silenced in drug-resistant cells, which may degrade
the inhibitory effect of WT1 on IGF1R transcription (65).
Similar effects are reected in the feedback loop between
Foxo3, IGF1R and AKT (31). Micro (mi) RNA inhibits IGF1R
expression by directly targeting the 3' untranslated regions
but CpG methylating the miRNA promoter region results in
the downregulation, and the loss of the inhibitory effects, of
IGF1R expression (66,67). MIR-143, MIR-503 and MIR-1271
regulate cisplatin resistance in human gastric cancer cell
lines by targeting IGF1R (66-69). Normally, insulin-like
growth factor binding protein-7 (IGFBP7) directly binds
to IGF1R and inhibits its function post-transcriptionally;
however, studies indicate that, in chemotherapy-resistant cells,
IGFBP7 expression signicantly decreased (70). Therefore,
IGF1R is overactivated once IGFBP7 inhibitory activity
has decreased (71). Furthermore, inactivating IGF1R inhibits
tumor cell proliferation by blockading G0/G1 and IGF1R binds
to non-IGF ligands from extracellular spaces, cell membranes
and the cytoplasm, which regulates cell proliferation and
survival IGF-independently during chemoresistance (72,73).
In addition to overexpression, IGF1R over-activation is
also important with respect to chemotherapeutic tolerance.
Phosphorylated IGF1R increased in chemotherapeutic
drug-resistant cell lines (74-76) and multiple mechanisms
contribute to the over-activation of IGF1R, including
increased constitutively secreted IGF-1 (63), transgelin
overexpression (77) and the effect of the Src oncogene on
IGF1R (78). By these processes, IGF1R signals promote tumor
cells to proliferate and induce resistance by over-activating
Grb2/RAS/RAF/MAPK cascades (64).
Inhibiting apoptosis. Anti-apoptosis is common to numerous
tumors and chemotherapy-resistant cells evolve diverse
strategies to limit or avoid apoptosis (3). The most common
strategy is to eliminate the tumor suppressor function of
p53 (79). Resistant cells also downregulate pro-apoptotic
Figure 1. IGF1R signaling pathway and its relevant drug resistance mechanisms: Promoting proliferation, inhibiting apoptosis and inducing changes to ABC
transporter proteins and the ECM. Silencing WT1 and mutant p53 causes loss of the inhibitory effects of the IGF1R promoter. Downregulating microRNAs,
including miR-143, miR-503, miR-1271, causes the loss of IGF1R mRNA degradation and IGF1R translation inhibitory activity. Serum insulin-like growth
factor binding proteins decrease the inhibitory effects of IGF1R post-transcriptionally, increasing IGF1R expression and activity. This may promote down-
stream phosphatidylinositol 3-kinase/protein kinase B and Grb2/RAS/RAF/mitogen-activated protein kinase signaling cascades, thereby enhancing cell
proliferation and anti-apoptotic activity. In addition, IGF1R signaling pathways participate in regulating ABC genes and alter cell responses to chemotherapy.
The ECM and IGF1R stabilize and activate the activity of one another. IGF1R, insulin-like growth factor 1 receptor; ABC, ATP-binding cassette; ECM,
extracellular matrix; WT1, Wilms tumor 1; miR, microRNA; Grb2, growth factor receptor bound protein 2.
YUA N et al: IGF1R AND CHEMOTHERAPEUTIC RESISTANCE
44
factors or increase the expression of anti-apoptotic factors to
avoid apoptosis (80). IGF1R participates in apoptosis inhibi-
tion predominantly via the PI3K/AKT signaling pathway in
drug-resistant cell lines but multiple other mechanisms are
associated with IGF1R overexpression and inhibition of apop-
tosis in drug-resistant cells (81,82).
Previous studies have indicated that cancer chemotherapy
is associated with inducing p53-dependent apoptosis
responses (79). p53 is one of the most frequently mutated tumor
suppressors and IGF1R overexpression inhibits wild-type p53
(WT-p53) via phosphorylated (p) AKT (80). This enhances the
ubiquitination-promoting function of murine double minute 2,
which decreases p53 protein production (79). Reciproca l l y,
WT-p53 renders tumor cells more chemosensitive by
inhibiting Sp1-induced transactivation of the IGF1R promoter
and increasing the expression of pro-apoptotic protein
p21 (81). Mutant p53 stimulates IGF1R promoter function in
chemotherapeutic resistant cell lines (82). Furthermore, IGF1R
regulates cisplatin resistance by targeting proto- oncogene Bcl‑2,
which is anti-apoptotic and affects drug resistance by binding
to and inhibiting Bcl 2-associated X protein (BAX) and Bcl 2
homologous antagonist killer protein (83). IGF1R activation
is also associated with decreased expression of IGFBP7,
which is associated with the expression of the anti-apoptotic
gene Bim and chemotherapy tolerance-associated genes,
including annexin A4 and protein kinase C 1 (84). Conversely,
overexpressing IGFBP7 induces apoptosis and reverses tumor
drug resistance (70).
Regulating ABC transporter proteins. The ABC is the largest
protein transporter superfamily present in all organisms (85).
This family of genes codes for different proteins (importers
and exporters) and its increased expression decreases
drug influx and increases efflux, decreasing therapeutic
response (86). IGF1R signals participate in regulating ABC
genes, including multidrug resistance protein 1 (MDR1),
MRP1, multidrug resistance-associated protein 2 (MRP2),
multidrug resistance-associated protein 3 (MRP3) and
breast cancer resistance protein (BCRP) (59,87-89). As such,
IGF1R increases tumor resistance by increasing the expres-
sion of MDR1, a protein implicated in chemotherapeutic
resistance (88). Expression of MRP3 and BCRP decreases
or disappears in the presence of an IGF1R inhibitor (87) and
overexpressing IGF1R results in increased MRP2 promoter
activity via increased pAKT and nuclear factor erythroid
2-related factor 2 in resistant cells (59,88). In addition,
IGF1R silencing increases chemotherapeutic sensitivity via
transcription inhibition of MRP-2 (59). Previous studies have
demonstrated that overexpressing IGF1R and MRP1 was asso-
ciated with chemotherapeutic resistance and poorer prognosis
compared with malignancies with normal or low expression
of IGF1R and MRP1, indicating that the co-expression of
IGF1R/MRP1 in tumors may predict chemotherapeutic
effects (88,89).
Interacting with ECM. The ECM is predominantly composed
of brin (collagen and laminin) and proteoglycans (hyaluronic
acid), which forms the structural framework for the majority
of tissues (90). The ECM transfer signals to the cells via inte-
grin binding and activation, which modulate cell proliferation,
survival and migration and inuence the tumor response to
anti-cancer therapies (91,92).
Previous studies have indicated that IGF1R stabilizes
the molecular structure of β1 integrin by protecting it from
proteasomal degradation and promoting tumor cells to grow
and proliferate (93). FAK, a substrate protein of IGF1R, is
activated by integrin, affecting epithelial transformation, inva-
sion and metastasis of tumor cells IGF1R-independently (38).
Extracellular bronectin increases the activity of β1 integrin
to increase the abundance of MAPK-phosphatase-1 and the
receptor of activated C kinase (RACK-1) (62). In addition,
establishing crosstalk between β1 integrin and IGF1R retains
the phosphorylation of IGF1R, which helps stimulate down-
stream signaling of IGF1R, and contributes to cell proliferation
and transformation (94). Previous studies have revealed that, in
the presence of IGF1R, the β1 integrin receptor increased the
recruitment of RACK-1 and mediated tumor cell migration (62).
These changes contribute to chemotherapeutic tolerance.
Other mechanisms. Previous studies have revealed that IGF1R
is sumoylated and translocated to the nucleus, which permits
the receptor to interact with chromatin, and function as a
transcriptional regulator (95-97). Nuclear IGF1R specically
binds to and functions as a transcriptional activator of its
own promoter, and interferes with signaling pathways (98).
Specifically, nuclear IGF1R interferes with Wnt signaling,
which upregulates ABC drug transporters and modulates drug
responses (99). Regarding the tumor microenvironment, acti-
vating IGF1R results in stabilizing hypoxia-inducible factor
(H I F)-1α and HIF-2α, and the upregulation of vascular endo-
thelial growth factor (100). A previous study demonstrated
that overexpressing HIF-1α increased the expression of Bcl-2,
decreased the expression of BAX, and induced the expression
of MDR1 and MRP1 (101). These results offer novel insights
into IGF1R-mediated chemotherapeutic resistance.
4. Conclusions
Chemotherapeutic resistance commonly results in cancer
treatment failing, with previous studies conrming multiple
resistance-associated mechanisms (102,103). Therefore,
understanding how tumors develop resistance may help to
identify improved drugs and increase patient survival rates.
Changes in drug transporter proteins, activating signaling
pathways and ineffectively inducing cell death are primary
mechanisms of chemotherapeutic resistance. IGF1R-mediated
resistance includes promoting cells to proliferate, inhibiting
apoptosis, inducing increased expression of ABC transporter
proteins on cell membranes and inducing changes in the ECM.
Transcription factors and miRNAs also intervene in regulating
IGF1R transcriptionally and cause downstream signaling path-
ways to excessively activate by promoting increased IGF1R
expression or loss of inhibitory effects to the IGF1R promoter.
IGFBPs participate in regulating IGF1R post-transcriptionally,
with the loss of IGF1R inhibition and enhanced expression
of anti-apoptotic and chemotherapy resistance-associated
genes. Following overexpression and over-activation, IGF1R
predominantly triggers the Grb2/RAS/RAF/MAPK and
PI3K/AKT cascades, which induce proliferation and inhibit
apoptosis in chemotherapy-resistant tumor cell lines. IGF1R
ONCOLOGY LETTERS 15: 41-47, 2018 45
signaling regulates the expression of ABC transporter proteins
via multiple mechanisms and renders chemotherapy less effec-
tive. The ECM interacts synergistically with IGF1R activity
as chemotherapy-resistant cells develop; however, how this
occurs remains unclear.
Overall, IGF1R signaling serves a crucial function in tumor
chemotherapeutic tolerance. Recently, drug combinations that
target predicted or identied chemoresistance markers have
been suggested as the future direction of cancer treatment. As
a membrane receptor, IGF1R is of particular interest in cancer
drug targeting; however, IGF1R-mediated resistance mecha-
nisms require further study. Furthermore, RTK heterodimer
and IGF1R nuclear translocation may be associated with drug
resistance, though few reports of this exist in the literature.
Acknowledgements
The present study was supported by the National Natural
Science Foundation of China (grant no. 81572411).
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