Actinomycin D and bortezomib disrupt protein homeostasis in Wilms tumor

Abstract

ABSTRACTWilms tumor is the most common kidney cancer in children, and diffusely 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. Furthermore, the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment by inducing apoptosis bothin vitroandin vivo. Lastly, we show that increased levels of proteasome components are associated with anaplastic histology and with worse prognosis in non-anaplastic Wilms tumor. In sum, maintaining protein homeostasis is critical for Wilms tumor proliferation, and it can be therapeutically disrupted by blocking protein synthesis or turnover.