Streptococcus vaginalis affects cellular dynamics of cervical cancer cells via oxidative stress-induced activation of endoplasmic reticulum unfolded protein response.

The vaginal microbiome plays an important role in the development of cervical cancer, highlighting the potential influence of specific members on disease susceptibility, progression, and suppression. In this study, we characterized a recently identified species of vaginal viridans group streptococci, Streptococcus vaginalis. By examining its prevalence, genomic features, and interactions with model cervical cancer cells, we aim to deepen the understanding of its biological significance and broader implications for vaginal health. Microbiome profiling detected S. vaginalis in 27 % of a cohort of Korean women, and the second most abundant species of Streptococcus. Pan-genome analysis and comparative genomics of S. vaginalis strains revealed their reduced pathogenic potentials. In vitro bioassays using cervical cancer cell models (HeLa, SiHa, and CaSki) demonstrated significant effects of S. vaginalis, influencing morphology, proliferation, migration, colony formation, and the induction of apoptosis. Mechanistic investigation identified the involvement of the endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR). Hydrogen peroxide produced by S. vaginalis was found to induce oxidative stress, triggering the ER stress-mediated cellular stress responses in cervical cancer cells. Our study revealed the influence of S. vaginalis on the dynamics of cervical cancer cells via oxidative stress-induced activation of the ER UPR pathway. These mechanistic insights emphasize a potential avenue for therapeutic interventions aimed at modulating oxidative and ER stress responses in cervical cancer treatment strategies. Overall, our findings provide new perspectives into the biological significance of S. vaginalis, expanding our understanding of its potential role beyond simple commensalism.