fig4

Figure 4. Mechanisms of enzalutamide and abiraterone acetate resistance in prostate cancer cells. Aberrant activation of PI3K/Akt pathway overexpressing p110β with loss of PTEN gene. Interaction of p85α subunits with Src kinase activates MAPK. Activated Akt overexpresses N-Myc, FOXO, ONECUT2 and EZH2 leads to activation of HIF1α, SMAD3, SOX2, and Nanog through suppressing TP53 and RB1. AR in the presence of hnRPA-1 forms AR-Vs and activates NF-κB signaling which in turn up-regulates IL-6 gene expression. Long-term exposure to antiandrogens significantly increases GR expression. Interaction of aberrant β-catenin of Wnt signaling to AR leads to expression target genes involved prostate cancer cell proliferation, tumor growth, stem cell marker expression, and chemotherapy drug resistance. Interaction of these genes with each other and with AR promotes enzalutamide/abiraterone acetate mediated neuroendocrine prostate cancer (NEPC) and castration resistant prostate cancer (CRPC) formation. PI3K: phosphatidylinositol-3 kinase; PTEN: phosphatase and tensin homolog; MAPK: mitogen-activated protein kinase; EZH2: enhancer of zeste homolog 2; HIF1α: hypoxia-inducible factors- α; SOX2: SRY-box transcription factor 2; TP53: tumor protein 53; RB1: retinoblastoma1; hnRPA-1: heterogeneous nuclear ribonucleoprotein A1; IL-6: interleukin-6; AR-vs: Androgen receptor variants; AR: androgen receptor; GR: glucocorticoid receptor; CRPC: castration resistant prostate cancer; NEPC: neuroendocrine prostate cancer; BCAF: B-cell activating factor; LT: Lymphotoxin-β; AURKA: Aurora kinase A