Proteasome inhibition sensitizes anaplastic Wilms tumor to actinomycin D

Wilms tumor is the most common kidney cancer in children, and anaplastic Wilms tumor is the most chemoresistant histological subtype. Here we explore how anaplastic Wilms tumor cells evade the common chemotherapeutic drug actinomycin D, which inhibits ribosomal biogenesis. We found that, when ribosomal capacity is limited by actinomycin D treatment, anaplastic Wilms tumor cells preferentially translate proteasome components and upregulate proteasome activity. Accordingly, increased proteasome levels are associated with anaplastic histology and with worse prognosis in Wilms tumor. Lastly, we show that the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment both in vitro and in vivo. Overall design: WiT49 cells were treated with actinomycin D (actD) or vehicle (DMSO), for varying lengths of time, in three replicates per condition, then subjected to ribosome profiling and RNA sequencing

肾母细胞瘤（Wilms tumor）是儿童最常见的肾脏恶性肿瘤，而间变性肾母细胞瘤（anaplastic Wilms tumor）是其中化疗耐药性最强的组织学亚型。本研究旨在探讨间变性肾母细胞瘤细胞如何逃避常见化疗药物放线菌素D（actinomycin D）的杀伤作用——该药物可通过抑制核糖体生物发生发挥抗肿瘤活性。研究发现，当放线菌素D处理限制了细胞核糖体功能容量时，间变性肾母细胞瘤细胞会优先翻译蛋白酶体组分，并上调蛋白酶体活性。据此，蛋白酶体水平升高与肾母细胞瘤的间变性组织表型及不良预后显著相关。最后，本研究证实蛋白酶体抑制剂硼替佐米（bortezomib）可在体外及体内实验中使肿瘤细胞对放线菌素D处理产生增敏效应。总体实验设计：将WiT49细胞分别用放线菌素D（actD）或溶剂对照二甲基亚砜（DMSO）处理不同时长，每个实验条件设置三次生物学重复，随后对细胞进行核糖体谱分析（ribosome profiling）及RNA测序。