Anti-cervical cancer activity of SRI-42127 via inducing DNA damage and activating p53, while reducing HuB, HuR, and HPV E6 E7 proteins

ABSTRACT: High-risk human papillomaviruses (HR-HPVs) drive 95% of cervical cancers (CaCx) and a significant fraction of other ano-genital and oropharyngeal cancers. Analyses of transcriptomes of normal and HPV-infected tissues have previously identified 95 differentially expressed RNA binding proteins known to associate with cancer-related pathways. One of them ELAVL2/HuB is a member of the ELAVL family, which includes the ubiquitous, well-studied ELAVL1/HuR. Elevated levels of HuR and HuB proteins have been reported in HPV cancers. However, information regarding their roles in HPV pathobiology is limited. SRI-42127, an inhibitor of HuR dimerization, essential for its activity, has shown promise in reducing the growth of glioblastoma xenografts. In this study, we explored the therapeutic potential of SRI-42127 to treat HPV-associated CaCx. Our findings demonstrate that HR-HPV E6 and E7 oncogenes regulate the abundance and subcellular localization of HuB and HuR proteins and that HuB interacts with HuR. SRI-42127 reduces HuR and HuB proteins and induces cell cycle arrest and apoptosis in CaCx cell lines. Unexpectedly, these effects are attributable to a previously unknown ability of SRI-42127 to induce DNA damage, which decreases HPV E6 and E7 proteins and stabilizes transcriptionally active p53. Mechanistically, HuB-knockdown induces DNA-damage and stabilizes p53. SRI-42127 curtails tumor growth of mouse HPV-16+ TC-1 transformed cells in syngeneic mice. Additionally, SRI-42127 complements cisplatin in inhibiting the growth of a CaCx cell line in 3D cultures and HPV-16+ CaCx PDX. Collectively, these findings suggest that SRI-42127 restores p53 functions in HPV+ CaCx and enhances sensitivity to conventional chemotherapies, potentially benefiting CaCx patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255374 | GEO | 2026/09/10

REPOSITORIES: GEO