Castration-resistant prostate cancer is resensitized to androgen deprivation by autophagy-dependent apoptosis induced by blocking SKP2

• Published in: Science signaling 2024-12, Vol.17 (867), p.eadk4122
• Main Authors: Celada, Sherly I, Li, Guoliang, Celada, Lindsay J, Kanagasabai, Thanigaivelan, Lu, Wenfu, Brown, LaKendria K, Mark, Zaniya A, Izban, Michael G, Ballard, Billy R, Zhou, Xinchun, Adunyah, Samuel E, Matusik, Robert J, Wang, Xiaofei, Chen, Zhenbang
• Format: Article
• Language: English
• Subjects: Androgen receptors; Androgens - metabolism; Animals; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Castration; Cell cycle; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Deprivation; Humans; Male; Mice; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; S-Phase Kinase-Associated Proteins - genetics; S-Phase Kinase-Associated Proteins - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1945-0877; 1937-9145; 1937-9145
• DOI: 10.1126/scisignal.adk4122

Resistance to androgen receptor (AR)-targeted therapies for prostate cancer (PCa) is characteristic of an aggressive subtype called castration-resistant prostate cancer (CRPC) and is often associated with tumor relapse. Both relapse and poor prognosis in patients with CRPC are associated with increased abundance of the E3 ubiquitin ligase SKP2. Therefore, we investigated the therapeutic potential of combined inhibition of AR and SKP2 for CRPC. We found that combined targeting of AR and SKP2 with small-molecule inhibitors decreased proliferation in two CRPC cell lines in culture and in xenografts in humanized mice. Furthermore, combined therapy in mice markedly decreased the growth of double-knockout tumors, a particularly invasive model of CRPC, whereas disruption of either AR or SKP2 alone only modestly suppressed their growth. Mechanistically, the inhibition of SKP2 in CRPC cells induced autophagy-dependent apoptosis and promoted luminal-associated phenotypes, which promoted responsiveness to AR-targeted therapy. These effects were further enhanced by coinhibition of AR and were not induced by the AR inhibitor alone. Our findings indicate that targeting both AR and SKP2 signaling pathways is necessary to treat CRPC.