Tacrolimus inhibits oral carcinogenesis through cell cycle control

Tacrolimus (TAC, FK506) is a major calcineurin inhibitor and has been commonly used in treatments of patients with organ transplants and immune diseases. Moreover, tacrolimus is recommended by the treatment guidelines for oral potentially malignant disorders (OPMDs) such as oral lichen planus (OLP). However, whether tacrolimus increases the risk of cancer remains controversial. We observed that in a 4-Nitroquinoline N-oxide (4NQO)-induced oral carcinogenesis model, tacrolimus treatment was associated with a significantly lower ratio of cancer formation (52.94% vs. 90%) and a lower proportion of Ki67 and proliferation cell nuclear antigen (PCNA) -positive cells in lesion areas (P < 0.001). Liver, kidney, and lung functions of rats and the tumor immune microenvironment of the tongue were not affected. These observations suggest that tacrolimus blocked oral carcinogenesis through epithelial cell proliferation inhibition, independent of its immunosuppressive effects. As a processing factor, tacrolimus decreased tumor formation and cell proliferation in different stages of oral squamous cell carcinoma (OSCC) progression in vivo and in vitro. Furthermore, we investigated effects on the cell cycle and expression of related proteins. Tacrolimus induced G1/S phase arrest and significantly downregulated the expression of cyclinD1, cyclinE1, and c-Myc. These results suggest that tacrolimus induces G1/S phase arrest via inhibition of cyclinD1, cyclinE1, and c-Myc expression and retards oral cell carcinogenesis in vitro and in vivo. Thus, application of tacrolimus is a safe therapeutic strategy for treating OPMDs.