Polyphyllin I Inhibits the Metastasis of Cervical Cancer Through the Regulation of the β-Catenin Signaling Pathway.

Cervical cancer ranks as the fourth most prevalent cancer and cause of cancer-related mortality among women globally. It exhibits a recurrence/metastasis rate of approximately 30% and a dismal 5-year survival of only 17% in metastatic cases. Despite significant advancements in surgical techniques, chemoradiotherapy, and targeted therapies, effective treatment options for metastatic cervical cancer remain limited. This study explored Polyphyllin I (PPI), which is a monomeric compound derived from the Rhizoma of Paris Polyphyllin, as a potential inhibitor of cervical cancer metastasis. Mechanistically, PPI directly interacted with β-catenin at the Ser552 site, inhibiting its phosphorylation and subsequent nuclear translocation, thereby suppressing TCF/LEF transcriptional activity and downstream EMT transcription factors (ZEB1, Slug, Snail, and Twist). Notably, PPI promoted β-catenin degradation via the autophagy-lysosomal pathway, as confirmed by CHX chase assays and the detection of the p62 and LC3 proteins, without altering the mRNA levels of β-catenin. In vitro experiments demonstrated that PPI effectively suppressed the migration and invasion of HO-8910PM cells by reversing the process of EMT. Additionally, PPI effectively inhibited TCF/LEF signaling, leading to a reduction in the transcription levels of EMT-associated transcription factors (EMT-TFs), which was mediated by the TCF/LEF family downstream of β-catenin. Furthermore, PPI exhibited inhibitory effects on proliferation, migration, and invasion in both HPV-positive (SiHa) and HPV-negative (C33A) cervical cancer cells. In vivo, PPI significantly suppressed peritoneal metastasis in a luciferase-labeled HO-8910PM xenograft mouse model. These findings reveal the dual role of PPI in blocking β-catenin signaling and inducing β-catenin depletion, thereby effectively restraining metastatic progression. This study underscores the potential of PPI as a promising therapeutic candidate for targeting cervical cancer metastasis through autophagy-mediated β-catenin regulation, offering a novel strategy to address current treatment limitations.