蛋白质类泛素化修饰调控膀胱癌化疗敏感性及其AR信号通路依赖机制研究

Bladder cancer is the most common urinary malignancy. Due to its recurrent nature, treatment of bladder cancer usually requires multidisciplinary approaches comprising adjuvant or neoadjuvant local or systematic chemotherapy in addition to surgical intervention. However, acquired chemoresistance is frequently observed and poses a significant challenge in the clinical setting. Androgen receptor (AR) signaling has been extensively studied and implicated in the development of chemoresistance in bladder cancer. Chemoresistant bladder cancer cells have been shown to express significantly elevated AR level when compared with isogenic cells. We previously found that a selective neddylation inhibitor, Pevonedistat, significantly repressed the expression of AR in AR positive bladder cancer cells, and exhibited synergistic inhibitory effect with cisplatin, a first-line chemo drug for bladder cancer, on the proliferation of AR positive bladder cancer cells. Therefore, we hypothesized that Pevonedistat could function as a chemo-sensitizer for bladder cancer through suppression of AR signaling pathway. To prove our hypothesis, multidisciplinary techniques and methods will be used to identify the key molecule(s) and elucidate the underlying mechanisms of how AR signaling pathway is regulated by neddylation. Chemo-sensitization property of Pevonedistat will be further investigated by in vitro and in vivo assays including but not limited to the use of patient derived xenografts (PDX) which we recently established. This project will provide a new insight and may offer new target(s) to the development of therapeutic compounds for chemo-resistant bladder cancer.

膀胱癌是最常见的泌尿系统肿瘤，因其易复发和进展特性，通常需要综合治疗，膀胱灌注化疗和全身化疗是除手术外最重要的治疗手段；而膀胱癌出现化疗耐药是临床上颇为棘手难题。雄激素受体（AR）信号通路已被大量研究证实与膀胱癌的发生和发展密切相关；文献报道AR阳性耐药膀胱癌细胞中AR的表达显著高于同源非耐药株；而AR可能通过多种作用机制介导膀胱癌化疗耐药。申请人前期研究发现，类泛素化抑制剂Pevonedistat可显著抑制AR阳性膀胱癌细胞中AR的表达，同时可增强顺铂对AR阳性细胞的增殖抑制作用。因此我们提出假设，Pevonedistat可能通过抑制膀胱癌细胞中AR表达而发挥对膀胱癌的化疗增敏效应。本项目中，我们拟采用多学科实验技术与方法，探索类泛素化修饰对膀胱癌AR信号通路的调控作用机制与关键分子、明确其介导膀胱癌细胞化疗增敏的作用及机制，为化疗耐药膀胱癌的临床治疗提供新研究思路和新靶点。

膀胱癌是最常见的泌尿系统肿瘤，因其易复发和进展特性，通常需要综合治疗，膀胱灌注化疗和全身化疗是除手术外最重要的治疗手段；而膀胱癌出现化疗耐药是临床上颇为棘手难题。雄激素受体（AR）信号通路已被大量研究证实与膀胱癌的发生和发展密切相关；文献报道AR阳性耐药膀胱癌细胞中AR的表达显著高于同源非耐药株；而AR可能通过多种作用机制介导膀胱癌化疗耐药。我们前期研究发现，类泛素化抑制剂Pevonedistat（MLN4924）可显著抑制AR阳性膀胱癌细胞中AR的表达，同时可增强顺铂对AR阳性细胞的增殖抑制作用。MLN4924可能通过抑制膀胱癌细胞中AR表达或其他途径而发挥对膀胱癌的化疗增敏效应。本项目中，我们采用了药理学、分子生物学、蛋白质学、免疫荧光化学、实验动物学、肿瘤干细胞和基因修饰等多学科实验研究技术与方法，研究类泛素化修饰对膀胱癌AR信号通路的调控作用机制与关键分子、明确了其介导膀胱癌细胞化疗增敏的作用及机制。MLN4924确能通过抑制膀胱癌细胞中AR的表达，增敏了AR阳性细胞对化疗药物顺铂的反应；MLN4924抑制膀胱癌细胞生长、集落形成、迁移、侵袭和诱导细胞凋亡和EMT，并且环氧化酶-2（COX-2）选择性抑制剂塞来昔布有增强MLN4924上述作用；MLN4924和塞来昔布联合能抑制AKT和ERK通路，其与膀胱癌化疗耐药密切相关。上述发现和研究为膀胱癌的药物治疗和有效控制膀胱癌复发与进展提供新方法和新治疗靶点。