Abstract Dysregulated ribosome biogenesis and p53 mutations are known to play oncogenic roles in various cancers, including pancreatic cancer (PanCa). In this study, we demonstrated the therapeutic potential of BMH-21, a pharmacological inhibitor of RNA polymerase I (Pol I), against PanCa by uncovering a novel molecular mechanism involving RPA194-mediated ubiquitination of mutant p53 without affecting the ubiquitination of WT p53. Our key findings include: (i) BMH-21 selectively induces apoptosis and cell growth inhibition of PanCa cells with no effect on normal human pancreatic ductal epithelial cells, (ii) BMH-21 degrades RPA194, (iii) BMH-21 inhibits recruitment of both RPA194 and RPA135 on rDNA to suppress pre-rRNA synthesis, (iv) RPA194 physically interacts with p53 and BMH-21-induced degradation of RPA194 selectively exposes truncated and mutated p53 for ubiquitination with no effect on ubiquitination of WT p53 in PanCa cells and (v) BMH-21 treatment significantly reduces the growth of orthotopic xenograft pancreatic tumors in athymic nude mice with no observed toxicity. Altogether, these findings suggest that BMH-21 is a promising, non-toxic therapeutic agent for PanCa patients with aberrant ribosome biogenesis and mutant p53, offering a potential new avenue for targeted treatment.
Ahmad et al. (Tue,) studied this question.