Figure 8. An updated model for AR intracellular trafficking and the mechanisms of CPPI targeting nuclear AR.

AR can be imported in the absence of androgens, and the imported AR will be efficiently polyubiquitinated and degraded via proteasomes in the nucleus. DHT binding enhances AR nuclear import and inhibits AR degradation in the nucleus. Once AR is in the nucleus, it will not be exported. After DHT withdrawal, unliganded AR will undergo degradation in the nucleus immediately (left). In CRPC cells, the increased nuclear AR stability will lead to AR nuclear localization. CPPI, a pyrroloimidazole, can block AR ligand binding, inhibit both androgen-induced and androgen-independent AR import, and act as a nuclear AR degrader in CRPC cells (right).