Tiburcio Patricia D B, Chen Kenian, Xu Lin, Chen Kenneth S
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Quantitative Biomedical Research Center, Peter O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Rep Med. 2025 May 20;6(5):102133. doi: 10.1016/j.xcrm.2025.102133. Epub 2025 May 9.
Wilms tumor is the most common pediatric kidney cancer, and diffuse anaplastic Wilms tumor is the most chemoresistant subtype. Here, we explore how Wilms tumor cells evade the chemotherapy actinomycin D, which inhibits ribosomal RNA biogenesis. Using ribosome profiling, protein arrays, and a genome-wide knockout screen, we describe how actinomycin D disrupts protein homeostasis and blocks cell-cycle progression. When ribosomal capacity is limited by actinomycin D treatment, anaplastic Wilms tumor cells preferentially translate proteasome components. Next, we find that the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment in vitro and prolongs survival in xenograft models. Lastly, increased levels of proteasome components are associated with anaplastic histology and worse prognosis in Wilms tumor patients. In sum, maintaining protein homeostasis is critical for Wilms tumor proliferation, and it can be therapeutically disrupted by blocking protein synthesis or turnover.
肾母细胞瘤是最常见的儿童肾癌，弥漫性间变性肾母细胞瘤是化疗耐药性最强的亚型。在此，我们探究肾母细胞瘤细胞如何逃避化疗药物放线菌素D（其可抑制核糖体RNA生物合成）。通过核糖体分析、蛋白质阵列和全基因组敲除筛选，我们描述了放线菌素D如何破坏蛋白质稳态并阻断细胞周期进程。当核糖体功能因放线菌素D处理而受到限制时，间变性肾母细胞瘤细胞会优先翻译蛋白酶体成分。接下来，我们发现蛋白酶体抑制剂硼替佐米在体外可使细胞对放线菌素D处理敏感，并延长异种移植模型中的生存期。最后，蛋白酶体成分水平升高与肾母细胞瘤患者的间变性组织学及较差预后相关。总之，维持蛋白质稳态对肾母细胞瘤增殖至关重要，通过阻断蛋白质合成或周转可在治疗上破坏这种稳态。
