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
Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA.
Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA.
Sci Signal. 2024 Dec 17;17(867):eadk4122. 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.
对前列腺癌（PCa）雄激素受体（AR）靶向治疗产生耐药性是一种名为去势抵抗性前列腺癌（CRPC）的侵袭性亚型的特征，且常与肿瘤复发相关。CRPC患者的复发和预后不良均与E3泛素连接酶SKP2丰度增加有关。因此，我们研究了联合抑制AR和SKP2对CRPC的治疗潜力。我们发现，用小分子抑制剂联合靶向AR和SKP2可降低两种CRPC细胞系在培养物中以及人源化小鼠异种移植物中的增殖。此外，小鼠联合治疗显著降低了双敲除肿瘤（一种CRPC的特别侵袭性模型）的生长，而单独破坏AR或SKP2仅适度抑制其生长。从机制上讲，抑制CRPC细胞中的SKP2可诱导自噬依赖性凋亡并促进管腔相关表型，从而增强对AR靶向治疗的反应性。AR的共同抑制进一步增强了这些效应，而单独的AR抑制剂不会诱导这些效应。我们的研究结果表明，靶向AR和SKP2信号通路对于治疗CRPC是必要的。
