Suppressing proteasome activity enhances sensitivity to actinomycin D in diffuse anaplastic Wilms tumor

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Wilms tumor is the most common pediatric kidney cancer.
• Diffuse anaplastic Wilms tumor is a highly chemoresistant subtype.
• Actinomycin D chemotherapy inhibits ribosomal RNA biogenesis, crucial for protein synthesis.

Purpose of the Study:

• To investigate the mechanisms by which Wilms tumor cells evade actinomycin D chemotherapy.
• To identify therapeutic strategies to overcome chemoresistance in anaplastic Wilms tumor.
• To explore the role of protein homeostasis in Wilms tumor proliferation and prognosis.

Main Methods:

• Ribosome profiling to assess protein translation.
• Protein arrays to analyze protein expression.
• Genome-wide knockout screens to identify resistance mechanisms.
• In vitro drug sensitivity assays.
• In vivo xenograft models to evaluate therapeutic efficacy.

Main Results:

• Actinomycin D disrupts protein homeostasis and cell-cycle progression in Wilms tumor cells.
• Anaplastic Wilms tumor cells prioritize translation of proteasome components under actinomycin D stress.
• The proteasome inhibitor bortezomib sensitizes Wilms tumor cells to actinomycin D.
• Bortezomib treatment prolonged survival in preclinical models.
• Elevated proteasome component levels correlate with anaplastic histology and poor prognosis in patients.

Conclusions:

• Maintaining protein homeostasis is essential for Wilms tumor cell proliferation.
• Targeting both protein synthesis and protein degradation pathways offers a potential therapeutic strategy.
• Therapeutic strategies aimed at disrupting protein homeostasis can overcome chemoresistance in Wilms tumor.