DIMETHYLFUMARATE MEDIATES CERVICAL CARCINOMA FERROPTOSIS THROUGH REDOX-RELATED PATHWAYS

Cervical cancer (CC) represents the fourth leading cause of women death worldwide. Development of CC is based on papillomavirus (HPV) persistent infections which boosts multistep transformation. CC has a high recurrence rate, and it is a relatively drug­resistant disease, indeed acquired resistance to cisplatin is frequently observed. Therefore, there is a need to identify novel drugs against CC. Dimethylfumarate (DMF) is a clinically approved treatment for psoriasis/multiple sclerosis and emerging studies also indicate DMF anti­tumor activity in some cancers [1]. DMF action involves both Nrf2­dependent and independent pathways. We demonstrate that DMF has an anti­proliferative effect in SiHa cells. In particular, we were interested in ferroptosis, a novel form of cell death mediated by iron­ dependent lipid peroxidation. We compared DMF effectiveness with different well­known inducers of ferroptosis by using cell viability and colony assays. Malondialdehyde and lipid peroxidation assays demonstrated that in SiHa cells, DMF induces ferroptotic­like cell death. Furthermore, we analyzed the expression of a group of ferroptosis­related genes. The results showed that mRNA levels of SAT1 (Spermidine/Spermine N1­Acetyltransferase 1) and PTGS2 (Prostaglandin­ endoperoxide synthase2), two well know markers of ferroptosis, were strongly increased upon DMF treatments. Since some studies reported that STAT3 and NRF2 are hyperactivated in tumors, and their interaction can regulate tumor progression, we focused on these pathways. Molecular analyses demonstrated that DMF can intercept both: it stimulates protective Nrf2 activity but also inactivates STAT3 that could finally sensitize these cells to ferroptosis. Our data albeit in its infancy, suggest therapeutic potentials of DMF for CC treatment and repurpose DMF­mediated strategies involving Nrf2­STAT3 cross talk as a promising option.