Thyroxine inhibits resveratrol-caused apoptosis by PD-L1 in ovarian cancer cells

Thyroid hormone, L-thyroxine (T-4), has been shown to promote ovarian cancer cell proliferation via a receptor on plasma membrane integrin alpha v beta 3 and to induce the activation of ERK1/2 and expression of programmed death-ligand 1 (PD-L1) in cancer cells. In contrast, resveratrol binds to integrin alpha v beta 3 at a discrete site and induces p53-dependent antiproliferation in malignant neoplastic cells. The mechanism of resveratrol action requires nuclear accumulation of inducible cyclooxygenase (COX)-2 and its complexation with phosphorylated ERK1/2. In this study, we examined the mechanism by which T-4 impairs resveratrol-induced antiproliferation in human ovarian cancer cells and found that T-4 inhibited resveratrol-induced nuclear accumulation of COX-2. Furthermore, T-4 increased expression and cytoplasmic accumulation of PD-L1, which in turn acted to retain inducible COX-2 in the cytoplasm. Knockdown of PD-L1 by small hairpin RNA (shRNA) relieved the inhibitory effect of T-4 on resveratrol-induced nuclear accumulation of COX-2- and COX-2/p53-dependent gene expression. Thus, T-4 inhibits COX-2-dependent apoptosis in ovarian cancer cells by retaining inducible COX-2 with PD-L1 in the cytoplasm. These findings provide new insights into the antagonizing effect of T-4 on resveratrol's anticancer properties.