Ubiquitination of oncogenic mutant p53 via attenuation of ribosome biogenesis machinery effectively inhibits pancreatic tumor growth

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.