TFF3 sensitizes cervical carcinoma cells to cisplatin toxicity by binding to IGF2R.

Cisplatin resistance causes ineffectiveness of cisplatin-based treatment for cervical carcinoma. The combination of cisplatin and other chemotherapeutic drugs is an available strategy to overcome this problem. However, chemotherapeutic drugs combined with cisplatin may show tissue toxicity and systemic side effects. Thus, there is a great need of seeking effective substitutes for these chemotherapeutic drugs to improve combination therapy. Here, we found that inactivating IL-6/JAK2/STAT3 signaling pathway sensitized carcinoma cells to cisplatin toxicity by increasing cisplatin accumulation, impairing DNA damage repair, and inhibiting the initiation and development of autophagy, which subsequently caused the increases in DNA damage levels and apoptosis rates in cisplatin-treated cells. We predicted that TFF3 negatively regulated transduction in the IL-6/JAK2/STAT3 pathway based on in silico analysis of the differentially expressed genes (DEGs) between highly trefoil factor 3(TFF3)-encoding mRNA-expressing carcinoma tissues and low-expressing counterparts, and experimentally determined that both ectopic expression of TFF3-encoding gene and TFF3 administration inhibited IL-6-induced STAT3 activation in carcinoma cells. Mechanistically, upon binding to IGF2R, TFF3 stabilized IGF2R by inhibiting the ubiquitin-proteasome degradation pathway to inactivate Akt and thereby STAT3. Moreover, we discovered that TFF3 administration antagonized protective effects of IL-6 stimulation against tumor-killing capacity of cisplatin. Based on these findings, we consider that TFF3 may be employed as a cisplatin sensitizer and have advantages over traditional chemotherapeutic drugs in cisplatin-based combination therapy, since it is a naturally occurring protein in cervical tissue.