Tiburcio Patricia D B, Chen Kenian, Xu Lin, Chen Kenneth S
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
Quantitative Biomedical Research Center, Peter O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX.
bioRxiv. 2024 Dec 17:2024.06.11.598518. doi: 10.1101/2024.06.11.598518.
Wilms tumor is the most common kidney cancer in children, and diffuse anaplastic Wilms tumor is the most chemoresistant histological subtype. Here, we explore how Wilms tumor cells evade the common chemotherapeutic drug 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. We found that, when ribosomal capacity is limited by actinomycin D treatment, anaplastic Wilms tumor cells preferentially translate proteasome components and upregulate proteasome activity. Based on these findings, we tested whether the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment. Indeed, we found that the combination induces apoptosis both and and prolongs survival in xenograft models. Lastly, we show that 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.
肾母细胞瘤是儿童最常见的肾癌，弥漫性间变性肾母细胞瘤是化疗耐药性最强的组织学亚型。在此，我们探究肾母细胞瘤细胞如何逃避常见化疗药物放线菌素D，该药物可抑制核糖体RNA生物合成。利用核糖体分析、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。我们发现，当核糖体能力因放线菌素D处理而受到限制时，间变性肾母细胞瘤细胞优先翻译蛋白酶体成分并上调蛋白酶体活性。基于这些发现，我们测试了蛋白酶体抑制剂硼替佐米是否能使细胞对放线菌素D处理敏感。事实上，我们发现联合用药在体外和体内均诱导细胞凋亡，并延长了异种移植模型中的生存期。最后，我们表明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。
