There are various kind of molecular pathways areplaying critical role to induce the development of cancer such as AR mediatedsignalling, PI3K/AKT pathway, NF-kB signalling, and etc. First of all, AR(androgen receptor) mediated signalling pathway is crucial to maintain thenormal function of prostate, helps to initiate and maintain spermatogenesis. ARis a member of steroid hormone receptor and composed of four functionaldomains, which are N-terminal domain (NTD), deoxyribonucleic acid-bindingdomain (DBD), ligand-binding domain (LBD) and short amino acid sequence. Therole of NTD is acts as transcription activator while DBD is to maintainintegrity of the dimerization and to stabilize AR-DNA complex. LBD is the sitewhich allows the steroid hormone to act on and short amino acid consists ofhinge region which segregate the LBD from DBD, including the function ofligand-dependent nuclear localization signal for AR nuclear transport.
Whenthere is no ligand, AR remains in the cytoplasm and associated with heat shockproteins and other chaperones. Vice versa, when ligand binds to AR, thiscomplex will trigger alteration in conformation of LBD, and this fosters theintramolecular and intermolecular interaction between N-terminal and C-terminaldomains. As a result, dimerization, phosphorylation and nuclear translocationcan occur. The complex within ligand and AR will recognize and bind to androgenresponse elements in promoter and enhancer regions of target genes which thenmodulate gene expression. The occurrence of prostate cancer is contributed byderegulation of AR signalling. Castration-resistant prostate cancer (CRPC)progression is due to overexpression of AR triggered by aberrantpost-translational modification, generation of AR splice variants and so on.Additionally, point mutation in AR increased AR activity drastically inprostate environment has made the ligand pool to be broader whereby AR canrespond to.
Moreover, growth factors like insulin-like growth factor-1 (IGF-1),VEGF and other cytokines advocates synergistic activities of AR and thisphenomenon can cause prostate cancer. At last, mutated co-repressors andco-activators molecules will galvanize AR activation and then develop intoprostate cancer.