Targeting Cancer-Associated PCNA with AOH1996 Induces Mitotic Catastrophe and Enhances Cisplatin Therapy in Cervical Cancer

Cervical cancers remain a significant health burden. Limitations on cervical cancer chemotherapeutic intervention caused by toxic side effects are a persistent barrier to care. In this study, we show that the human papillomavirus oncogenes that cause most cervical cancers also increase the levels of a cancer-associated isoform of proliferating cell nuclear antigen (PCNA) known as caPCNA. The abundance of caPCNA is specifically elevated in cervical cancer. Similar to observations in other cancers, we found that a small-molecule inhibitor of caPCNA (AOH1996) selectively killed cell line, organoid, and xenograft models of cervical cancer. Our subsequent molecular analysis identified a novel ability of AOH1996 to induce cell death by disrupting the interaction between PCNA and γ-tubulin, resulting in mitotic arrest. We show AOH1996 selectively induces mitotic death in transformed cells, because these cells attempt to progress through mitosis, rather than decondensing their chromosomes and reforming their nuclear membranes like untransformed control cells. Furthermore, we show that these differences allow AOH1996 to specifically sensitize cervical cancer cells to cisplatin, a frontline chemotherapeutic used to treat cervical cancer. We found that subtherapeutic doses of AOH1996 and cisplatin could reduce cervical cancer xenograft growth and improve survival, similarly to a therapeutic dose of cisplatin without the cisplatin-induced toxicity that restricts care. To our knowledge, this study provides the first evidence that AOH1996 can function as a cisplatin-sensitizing agent in cervical cancer models. SIGNIFICANCE: We identify a novel mechanism by which the small-molecule inhibitor AOH1996 targets cancer-associated PCNA to induce mitotic death in cervical cancer cells. By disrupting PCNA:γ-tubulin interactions, AOH1996 selectively sensitizes tumors to a lower dose of cisplatin, enabling effective therapy with reduced toxicity and suggesting a potential strategy to reduce treatment-associated toxicity.