Thyroid hormone, l-thyroxine (T4), has been shown to promote ovarian cancer cell proliferation via a receptor on plasma membrane integrin αvβ3 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 αvβ3 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 T4 impairs resveratrol-induced antiproliferation in human ovarian cancer cells and found that T4 inhibited resveratrol-induced nuclear accumulation of COX-2. Furthermore, T4 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 T4 on resveratrol-induced nuclear accumulation of COX-2- and COX-2/p53-dependent gene expression. Thus, T4 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 T4 on resveratrol’s anticancer properties.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Cancer Research
Chin, Y. T., Wei, P. L., Ho, Y., Nana, A. W., Changou, C. A., Chen, Y. R., Yang, Y. C. SH., Hsieh, M. T., Hercbergs, A., Davis, P. J., Shih, Y. J., & Lin, H. Y. (2018). Thyroxine inhibits resveratrol-caused apoptosis by PD-L1 in ovarian cancer cells. Endocrine-Related Cancer, 25(5), 533-545. https://doi.org/10.1530/ERC-17-0376