IGFBP3 and cisplatin synergistically suppress HeLa cell proliferation and migration through NRF2 inhibition.

Background and purpose: Cisplatin is a cornerstone of cervical cancer treatment, but chemoresistance and toxicity limit its efficacy. The NRF2-mediated antioxidant pathway contributes to cisplatin resistance. This study investigated whether insulin-like growth factor-binding protein 3 (IGFBP3) could enhance cisplatin efficacy by suppressing NRF2 signaling. Experimental approach: HeLa cervical cancer cells were treated with IGFBP3, cisplatin, or their combination. Cytotoxicity and drug synergy were evaluated using the MTT assay and combination index analysis. Oxidative stress markers and antioxidant enzyme activities were assessed. NRF2 protein expression was determined by Western blotting and ELISA. Cell migration was evaluated using a scratch assay, and NRF2 target gene expression was measured by RT-qPCR. Findings/Results: IGFBP3 combined with cisplatin produced synergistic cytotoxicity (combination index <1). Compared with either monotherapy, the combination significantly suppressed NRF2 expression, increased oxidative stress, reduced antioxidant enzyme activities, and inhibited cell migration. Expression of NRF2 target genes, including HO-1, CAT, SOD, and GPX, was also downregulated. Conclusion and implications: IGFBP3 synergized with cisplatin to inhibit cervical cancer cell proliferation and migration, at least partly through suppression of the NRF2-mediated antioxidant pathway. IGFBP3 may therefore represent a promising chemosensitizing agent for overcoming cisplatin resistance and warrants further preclinical investigation.