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.