A novel peptide explicitly induces prostate cancer cell death by destabilizing AR and inhibiting AR-mediated transcription.

Current treatment strategies for prostate cancer primarily focuses on regulating androgen receptor (AR) activity, either through androgen deprivation or the use of anti-androgen therapies. While these approaches are initially effective, many patients eventually develop resistance, resulting in the emergence of castration-resistant prostate cancer (CRPC). This transition not only complicates disease management but also leads to persistent side effects, underscoring the urgent need for alternative therapeutic strategies that directly target AR or disrupt its interactions with co-regulatory proteins. Given the deregulated expression and altered subcellular localization of TIP60, a key AR coregulator in prostate cancer, we hypothesized that interfering with the AR-TIP60 interaction could mitigate aberrant AR signaling. To investigate this, we selectively expressed the C-terminal region of TIP60 containing the nuclear receptor box (NRB) motif as a short peptide in prostate cancer cells and demonstrated that this peptide effectively disrupts the AR-TIP60 interaction and exerts broad suppressive effects on AR signaling. Importantly, the peptide selectively induces cell death in AR-positive prostate cancer cells. Mechanistic studies revealed that the peptide impairs AR signaling by inhibiting dihydrotestosterone (DHT)-mediated AR chromatin binding and promoting AR degradation via the proteasome pathway. Furthermore, in silico analyses suggest that the peptide directly binds to AR's N-terminal domain, leading to its structural destabilization. Collectively, these results identify a novel AR-targeting peptide with multifaceted inhibitory effects, offering a promising therapeutic avenue for AR-positive prostate cancers, particularly in treatment-resistant cases. The peptide holds potential for development as a standalone therapy or in combination with existing chemotherapeutic agents.