Resveratrol antagonizes thyroid hormone-induced expression of checkpoint and proliferative genes in oral cancer cells

BACKGROUND/PURPOSE: Dysregulation of cell cycle checkpoint control may lead to the independence of growth regulating signals. Checkpoint protein such as the PD-1/PD-L1 immune checkpoint involving tumor cells and host immune defense lymphocytes is a well-studied therapeutic target in oncology. Acting at a cell surface receptor on plasma membrane integrin αvβ3, thyroxine stimulates intracellular accumulation of PD-L1 in cancer cells. Although resveratrol also binds to integrin αvβ3, it reduces PD-L1 expression. MATERIALS AND METHODS: In current studies, we investigated the roles of resveratrol and thyroxine in regulating expression of proliferation-related genes and checkpoint genes, PD-L1, BTLA in two oral cancer cell lines. RESULTS: Thyroxine suppressed the expression of pro-apoptotic BAD but induced proliferative CCND1 expression in SSC-25 cells and OEC-M1 cells. It activated expression of PD-L1 and BTLA in both cell lines. On the other hand, resveratrol suppressed the expression of all. Alternatively, it activated BAD expression. Thus thyroxine induces checkpoint gene expression which may promote proliferation in cancer cells. Alternatively, resveratrol reverses the stimulatory effects of thyroid hormone to induce anti-proliferation. CONCLUSION: These findings provide new insights into the antagonizing effect of resveratrol on the thyroxine-induced expression of checkpoint genes and proliferative genes in oral cancers.