Cytokine dysregulation
Dysregulation of cytokines secreted
by cancer cells, including chemokines, growth factors, pro-angiogenic
factors, anti-angiogenic factors, adipokines, soluble receptors and
extracellular proteases, and their associated stroma are associated with
drug resistance in many diseases (Jones, Huang et al., 2016). PCa cells
express autocrine interleukin-6 (IL-6), which is a frequently studied
pro-inflammatory cytokine with respect to Enz resistance. IL-6 activates
the Janus kinase
(JAK)/STAT3
pathway, which is associated with prostate tumour growth and
progression. The
IL6-STAT3
axis was previously validated as a mediator of resistance to Enz, and
the STAT3 inhibitor AG490 reverses ENZ resistance in CRPC (Culig and
Puhr, 2018 , Canesin, Krzyzanowska et al., 2020 , Liu, Zhu et al.,
2014). In addition, Enz increased high mobility group box 1 (HMGB1)
levels promote tumour-associated macrophage (TAM) recruitment and
polarization. Activated TAMs secrete IL-6 to enhance Enz-induced NED and
directly facilitate HMGB1 transcription via STAT3. Hence,
blocking the feedback loop between neuroendocrine differentiation
factors and TAMs by targeting IL-6-STAT3 with tocilizumab and HMGB1
silencing may be a potential method for overcoming Ent resistance (Wang,
Peng et al., 2018). Leukaemia inhibitory factor (LIF) and oncostatin M
(OSM) are IL-6-like cytokines that are increased in the prostate
epithelial cells of cancer patients. LIF activates STAT3 to promote CRPC
and NED, while OSM induces morphological changes, the EMT, and migration
of PCa cells via the JAK/STAT3 pathway. Similarly, IL-8 and IL-11
promote PCa cell progression through STAT3 signalling (Canesin,
Krzyzanowska et al., 2020).
IL-23 is a driver of CRPC that is generated by myeloid-derived
suppressor cells (MDSCs). MDSC infiltration and IL-23 were increased in
blood and tumour samples from CRPC patients. IL-23 directly acted on the
pSTAT3-RORγ axis to drive AR and its splicing variants and downstream
target gene transcription. Combined, anti-IL-23 and Enz can effectively
inhibit AR activity and induce tumour cell apoptosis. Thus, blocking
MDSC recruitment to the tumour or inhibiting IL-23 can be potential
therapeutic strategies for Enz-resistant CRPC patients (Calcinotto,
Spataro et al., 2018).
The C-X-C motif chemokine ligand 12 (CXCL12) and its receptor CXCR4 are
overexpressed in prostate cancer cells and tissues and are associated
with tumour progression. The intracellular CXCL12γ
isoform was found to be expressed in
CTCs of m-CRPC patients and PCa cells with neuroendocrine phenotypes.
The overexpression of CXCL12γ induced CSC and neuroendocrine phenotypesvia CXCR4-mediated protein kinase C/NFκB signalling, leading to
tumour progression and drug resistance (Jung, Cackowski et al., 2018).
The seven-transmembrane G protein–coupled chemokine receptor
CXCR7 was the most upregulated gene
in Enz-resistant CRPC and was directly regulated by AR. Elevated CXCR7
interacted with β-arrestin 2, which recruited mitogen-activated protein
kinase (MAPK) proteins to phosphorylate extracellular regulated protein
kinase (ERK) 1/2. MAPK/ERK inhibitors have been shown to be effective in
suppressing Enz-resistant CRPC. Moreover, macrophage migration
inhibitory factor (MIF), a ligand for CXCR7, induced the expression of
cell cycle genes by activating the AKT pathway. The MIF/CXCR7/AKT
signalling pathway facilitated CRPC growth and metastasis independent of
the CXCL12/CXCR4 axis. In addition, interleukin-8 (IL-8) secretion and
vascular endothelial growth factor (VEGF) were upregulated by CXCR7,
leading to tumour angiogenesis.
CXCR7 also has been reported to
interact with the epidermal growth receptor (EGFR) and stimulate
increased levels of phospho-EGFR (p-EGFR). The effect of the combination
of CXCR7 inhibitors and Enz was manifested by significant growth
inhibition of PCa cell line xenografts and PDX models of CRPC (Li, Fong
et al., 2019 , Rafiei, Gui et al., 2019 , Luo, Azad et al., 2018).
Similarly, other cytokines, such as fibroblast growth factor,
granulocyte-macrophage colony-stimulating factor, and IL-10, were found
to be elevated in the circulation of mCRPC patients resistant to Enz
(Pal, Moreira et al., 2019).
MicroRNAs
and Enz resistance
MicroRNAs (miRNAs) are short endogenous RNA molecules consisting of
19-25 nucleotides that regulate gene expression after transcription. It
has been reported that miRNAs function as oncogenes or tumour
suppressors in cancer. In particular, miRNAs have been shown to be
involved in the regulation of cellular responses to drugs (Si, Shen et
al., 2019). In CRPC, miR-346, miR-361-3p, and miR-197 have been proven
to augment AR activity via a novel mechanism by which a 6.9-kb AR
is directly associated with the 3′UTR to stabilize the transcripts,
which are increased after long-term Enz treatment (Fletcher, Sulpice et
al., 2019). MicroRNA-194 (miR-194) functions as a novel
post-transcriptional regulator of trans-differentiation in prostate
cancer and is negatively correlated with signal-axis AR. Notably,
miR-194 trans-differentiated PCa cells into a neuroendocrine-like cell
by targeting FOXA1, which may contribute to Enz resistance (Fernandes,
Toubia et al., 2019).
The loss of miR-101 or miR-27a during the progression of PCa contributed
to the upregulation of orphan nuclear receptor COUP-TFII expression,
which in turn upregulated the expression of the forkhead domain
transcriptional factor FOXM1 and structural protein of kinetochore
CENPF, two of the most important oncogenes in PCa.
The expression of miR-101 or miR-27a
was drastically decreased in Enz-resistant clones,
while overexpression of miR-101 or miR-27a increased the efficacy of Enz
treatment (Lin, Kao et al., 2016). The expression of
miR‐30c‐1‐3p/miR‐103a‐2‐5p was significantly downregulated in PCa cells.
MiR‐30c‐1‐3p/miR‐103a‐2‐5p
overexpression inhibited the expression of AR‐V7, which was directly
bound to the AR‐V7 3′‐UTR, suppressing CRPC cell proliferation.
Importantly, the effects of miR‐30c‐1‐3p/miR‐103a‐2‐5p overexpression
was significantly reversed by AR‐V7 overexpression upon Enz treatment
(Chen, Yao et al., 2019). Targeting miR‐30c‐1‐3p/miR‐103a‐2‐5p may be a
selective method of Enz-resistant therapy.
MiR-644a is a broad-spectrum cellular pathway regulator that
downregulates the expression of multiple tumour microenvironment
drivers, including AR coregulators, c-MYC, BCL-XL, and BCL-2.
Importantly, miR-644a contributes to the downregulation of EMT markers
and the elevation of E-cadherin. In addition, the Warburg effect is
suppressed by miR-644a via collective inhibition of c-Myc, AKT,
IGF1R, and GAPDH expression. In particular, experiments have shown that
miR-644a sensitized tumours to Enz therapy. Thus, miR-644a can function
as an auxiliary agent in the treatment of Enz resistance (Ebron, Shankar
et al., 2019).
Genepolymorphisms
In recent years, a number of studies have focused on the association
between single nucleotide
polymorphisms (SNPs) in androgen-related genes and
prognoses. Several SNPs also had impacts on CRPC progression and
overall patient survivalc
(Aragon, Cendon et al., 2019). Despite their roles in tumour
development, there was a link between SNPs and Enz resistance. Y-box
binding protein-1
(YB-1)
is a critical factor in CRPC progression because it regulates the
expression of AR-V7. Inhibiting YB-1 enhanced the effect of Enz in CRPC.
The (rs12030724 polymorphism in the YB-1 gene affected the expression of
YB-1 in PCa tissues (YB-1 positive rate was 14.3% in TT, 40.0% in AT,
and 52.9% in AA, P = 0.04) and the probability of metastatic prostate
cancer progression (AT/TT vs AA, hazard ratio = 0.49, 95% confidence
interval = 0.32 to 0.77, P = 0.001) (Shiota, Fujimoto et al., 2016). In
another experiment, researchers investigated genetic polymorphisms in
several antioxidant enzymes that were involved in regulating various
stimulus-induced oxidative stress states to modulate AR and CRPC
progression. Only the GSTM3 rs7483 SNP was associated with significant
progression risk (AG/GG versus AA; HR; [95% CI], 0.45
[0.25–0.79], P = 0.0047). The levels of intracellular reactive
oxygen species and GSTM3 expression were upregulated in both
castration-resistant and Enz-resistant cells (Shiota, Fujimoto et al.,
2017 , Fujimoto, Shiota et al., 2017).
According to an ARMS-PCR analysis of
the androgen receptor-coding gene in 50 patients with drug-resistant PCa
and 50 patients with non-drug-resistant PCa
in the human population
of the Isfahan province, Enz resistance was significantly correlated
with the rs137852595 SNP (P-value =
0.005) and rs137852574 SNP (P-value = 0.039). In patients with these
SNPs, the binding of the drug to the active site of AR was inaccurate,
leading to a reduction in the binding energy of the drugs with the
receptors (Alizadeh, Sazegar et al., 2018 , Kaviani, Sazgar et al.,
2018).