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. 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