Figure 3 | Activation of Wnt signalling. Wnt proteins
bind to FZD and coreceptors, including LRP4, LRP5, LRP6, ROR1, ROR2, and
RYK. Canonical Wnt signalling pathway contain β-catenin and
β-catenin-related pathways while noncanonical Wnt signalling pathway
include Ca2+, Rho, and Rac pathways. Notably, WLS have
multiple functions in regulating Wnt and AR signalling. FZD,
transmembrane frizzled; LRP, low-density lipoprotein receptor; ROR,
tyrosine-protein kinase transmembrane receptor; RYK, tyrosine-protein
kinase; GSK-3β, glycogen synthase kinase-3β; SOX9, sex-determining
region Y(Sry)-related high-mobility group (HMG) box 9; PRKAR2B, a
oncogenic gene of tetrameric enzyme PKA; CWP232291, Wnt/β-catenin
inhibitor; CHOP, pro-apoptotic transcription factor; DVL, Dishevelled;
Rho and Rac, two branches of planar cell polarity pathway; MAP3Ks,
mitogen-activated protein kinase kinase kinases; MAPKK,
mitogen-activated protein kinase kinase; DAAM, Dishevelled associated
activator of morphogenesis; ROCK, Rho-associated kinase; JNK, c-Jun
N-terminal kinase; PKC, protein kinase C; CaMKII,
Ca2+/calmodulin-dependent kinase type II; PLC, phospholipase C; Y27632,a
ROCK inhibitor; WLS, Wntless.
Glycolysis
Normally, differentiated cells rely on mitochondrial oxidative
phosphorylation to produce the energy needed for cellular processes.
However, most cancer cells depend on aerobic glycolysis. This
cancer-related change in metabolism is known as the “Warburg effect”.
Cancer cells are inclined to convert
most glucose to lactate regardless of whether oxygen is present (Heiden,
Cantley et al., 2009). In prostate cancer, AR regulates genes related to
glucose consumption and biomass production. Moreover, androgens increase
the activity of several glycolytic enzymes, such as hexokinase-2 and
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2. Androgens
contribute to glycolysis via calcium/calmodulin-dependent protein
kinase kinase beta activating AMP-activated protein kinase (AMPK)
(Gonzalez-Menendez, Hevia et al., 2018). Glucose transporters (GLUTs)
are upregulated in PCa cells. GLUT1 is a GLUT family member and is
associated with poor prognosis (Wang, Xu et al.,
2020).
The GLUT1 gene promoter directly binds to AR, which promotes GLUT1
transcription. GLUT1 may act as a potential target, and the combination
of a GLUT1 inhibitor and Enz may suppress CRPC cell proliferation and
glycolysis and induce apoptosis. A previous study demonstrated that
genes involved in regulating glucose metabolism were altered in LNCaP
cells overexpressing NF-κB2/p52 (p52), leading to the enhancement of
glucose flux for glycolysis and resistance to Enz (Cui, Nadiminty et
al., 2014).
Hypoxia is the pathological feature of solid tumours and contributes to
the invasion of cancers. Clinical evidence indicates that hypoxia and
hypoxia-inducible factor (HIF) may play vital roles in CRPC development
and treatment resistance (Bharti, Kakkad et al., 2019). Geng et al.
established a molecular model in which androgen/AR independence and
therapy resistance may both be due to the successful blockade of the
androgen/AR axis (by ADT, Enz, or siRNA, etc.) under hypoxia (Geng, Xue
et al., 2018). They found that glucose-6-phosphate isomerase (GPI) was
inhibited by AR transcription under hypoxia but was recovered and
increased upon AR inhibition. GPI maintained glucose metabolism and
energy homeostasis under hypoxia by shifting the glucose flux from the
androgen/AR-dependent pentose phosphate pathway to the hypoxia-induced
glycolysis pathway, resulting in a decrease in the growth inhibition of
Enz. Hence, targeting GPI may improve the therapeutic effect of Enz and
is a novel method to overcome drug resistance.