The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Department of Pharmacy, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Cancer Res. 2021 Feb 15;81(4):1026-1039. doi: 10.1158/0008-5472.CAN-20-1965. Epub 2020 Dec 4.
The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer. However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms of this resistance are not fully defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant prostate cancer cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling prostate cancer cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target. SIGNIFICANCE: These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlights cotargeting KIF15 and AR as a therapeutic strategy for these tumors.
新一代雄激素受体 (AR) 通路抑制剂恩扎卢胺可延长转移性前列腺癌患者的生存期。然而，这些患者不可避免地会对恩扎卢胺产生耐药性，其耐药机制尚不完全明确。本文中，我们证明驱动蛋白家族成员 15 (KIF15) 通过增强前列腺癌细胞中的 AR 信号来促进恩扎卢胺耐药性的产生。KIF15 可直接与 AR/AR-V7 的 N 端结合，并通过增加泛素特异性蛋白酶 14 (USP14) 与 AR/AR-V7 的蛋白缔合，来阻止 AR/AR-V7 蛋白降解。反过来，具有转录活性的 AR 又会刺激 KIF15 的表达。KIF15 抑制剂单独或与恩扎卢胺联合使用，可显著抑制恩扎卢胺耐药性前列腺癌细胞的生长和异种移植瘤的进展。这些发现强调了 KIF15 在使前列腺癌细胞对恩扎卢胺产生耐药性方面的关键作用，并将 KIF15 合理化作为一种潜在的治疗靶点。
这些发现表明 KIF15 和 AR 之间的相互激活如何促进前列腺癌对恩扎卢胺产生耐药性，并强调了靶向 KIF15 和 AR 作为这些肿瘤的治疗策略。
