Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China.
Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China.
J Biol Chem. 2021 Jan-Jun;296:100276. doi: 10.1016/j.jbc.2021.100276. Epub 2021 Jan 9.
The clinical efficacy of docetaxel (DTX) in prostate cancer treatment is barely satisfactory due to diverse responses of the patients, including the development of resistance. Recently, aberrant androgen receptor (AR) signaling, including expression of the constitutively active ARV7, was reported to contribute to DTX resistance. However, the underlying molecular mechanism remains largely unknown. Of note, previous studies have highlighted that ARV7, unlike its parental AR, potentially favors the expression of some genes involved in cell cycle progression. Since DTX mainly targets microtubule dynamics and mitosis, we wanted to test whether ARV7 plays a specific role in mitotic regulation and whether this activity is involved in DTX resistance. In the present study, we found that ARV7 mediates DTX sensitivity through inactivating the spindle assembly checkpoint (SAC) and promoting mitotic slippage. By shifting the balance to the slippage pathway, ARV7-expressing cells are more likely to escape from mitotic death induced by acute DTX treatment. Furthermore, we also identified E2 enzyme UBE2C as the primary downstream effector of ARV7 in promoting the SAC inactivation and premature degradation of cyclin B1. Moreover, we showed that combination treatment of DTX and an inhibitor of mitotic exit can exert synergistic effect in high ARV7-expressing prostate cancer cells. In sum, our work identified a novel role of ARV7 in promoting DTX resistance and offering a potential path to combat DTX resistance related to abnormal activation of the AR signaling and mitotic dysregulation.
由于患者的反应不同，包括产生耐药性，多西紫杉醇（DTX）在前列腺癌治疗中的临床疗效并不令人满意。最近，研究表明异常的雄激素受体（AR）信号，包括组成型激活的 ARV7 的表达，与 DTX 耐药性有关。然而，其潜在的分子机制在很大程度上仍不清楚。值得注意的是，先前的研究强调，与亲本 AR 不同，ARV7 可能有利于某些与细胞周期进程相关的基因的表达。由于 DTX 主要靶向微管动力学和有丝分裂，我们想测试 ARV7 是否在有丝分裂调节中发挥特定作用，以及这种活性是否与 DTX 耐药性有关。在本研究中，我们发现 ARV7 通过失活纺锤体组装检查点（SAC）和促进有丝分裂滑向来介导 DTX 敏感性。通过将平衡转移到滑溜途径，表达 ARV7 的细胞更有可能逃避由急性 DTX 处理引起的有丝分裂死亡。此外，我们还确定了 E2 酶 UBE2C 作为 ARV7 的主要下游效应物，在促进 SAC 失活和周期蛋白 B1 的过早降解中发挥作用。此外，我们表明 DTX 和有丝分裂退出抑制剂的联合治疗可以在高 ARV7 表达的前列腺癌细胞中发挥协同作用。总之，我们的工作确定了 ARV7 在促进 DTX 耐药性方面的新作用，并提供了一种潜在的途径来对抗与 AR 信号异常激活和有丝分裂失调相关的 DTX 耐药性。
