Ribonuclease 3 from human gut-derived Streptomyces sp. BI87 suppresses colorectal cancer by inhibiting ribosome biogenesis

Objective:We aim to identify and characterize the anticancer component in the metabolites of the gut bacterium Streptomyces sp. BI87, validate its inhibitory effects on cancer and elucidate the mechanism underlying its cancer-suppressive activities.Design:We conducted in vitro experiments to assess the suppressive effects of BI87 culture supernatant and a cloned BI87 component, RNase3, on the proliferation, migration and invasiveness of human colorectal cancer (CRC) cell lines RKO, HCT116 and LoVo, with the non-cancerous gut epithelial cell line NCM460 as a control. Therapeutic relevance was examined in an inflammation-driven AOM/DSS CRC mouse model and the MC38 allograft tumor model. To elucidate the molecular events and mechanisms underlying the therapeutic effects of the BI87 products, we compared proteomes between CRC tissues with or without treatment by the BI87 products to identify the pathways contributing to the CRC pathogenesis and the therapeutic effects of the BI87 products.Results:BI87 metabolites potently suppressed CRC activities and promoted apoptosis. In the AOM/DSS mouse CRC model, BI87 reduced tumor burden, alleviated mucosal injury and improved barrier integrity, and these effects were reproduced by the cloned RNase3. In the MC38 allograft CRC model, BI87 culture supernatant and RNase3 both slowed tumor growth without detectable differences in body weight during treatment. Mechanistically, proteomic cross-analysis converged on the ribosome biogenesis pathway and Western blots confirmed the downregulation of Bms1, Rrp7a and UTP21.Conclusion:BI87 exerts robust anticancer activity largely mediated by its secreted RNase3, which suppresses tumor growth by inhibiting eukaryotic ribosome biogenesis via Bms1/Rrp7a/UTP21 downregulation.