Thyroid hormone-induced expression of inflammatory cytokines interfere with resveratrol-induced anti-proliferation of oral cancer cells

Yi-Ru Chen; Yu-Shen Chen; Yu-Tang Chin; Zi-Lin Li; Ya-Jung Shih; Yu-Chen S H Yang; Chun A ChangOu; Po-Yu Su; Shwu-Huey Wang; Yun-Hsuan Wu; Hsien-Chung Chiu; Sheng-Yang Lee; Leroy F Liu; Jacqueline Whang-Peng; Hung-Yun Lin; Shaker A Mousa; Paul J Davis; Kuan Wang

doi:10.1016/j.fct.2019.110693

Thyroid hormone-induced expression of inflammatory cytokines interfere with resveratrol-induced anti-proliferation of oral cancer cells

Food Chem Toxicol. 2019 Oct:132:110693. doi: 10.1016/j.fct.2019.110693. Epub 2019 Jul 20.

Authors

Yi-Ru Chen¹, Yu-Shen Chen², Yu-Tang Chin³, Zi-Lin Li¹, Ya-Jung Shih¹, Yu-Chen S H Yang⁴, Chun A ChangOu⁵, Po-Yu Su⁶, Shwu-Huey Wang⁷, Yun-Hsuan Wu⁸, Hsien-Chung Chiu⁹, Sheng-Yang Lee¹⁰, Leroy F Liu¹¹, Jacqueline Whang-Peng¹², Hung-Yun Lin¹³, Shaker A Mousa¹⁴, Paul J Davis¹⁵, Kuan Wang¹

Affiliations

¹ Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei, 11031, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei, 11031, Taiwan.
² Department of Pediatrics, E-Da Hospital, Kaohsiung, 82445, Taiwan; School of Medicine, I-Shou University, Kaohsiung, 84001, Taiwan.
³ Taipei Cancer Center, Taipei Medical University, Taipei, 11031, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, 11031, Taiwan.
⁴ Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, 11031, Taiwan.
⁵ Core Facility Center, Office of Research and Development, Taipei Medical University, Taipei, 11031, Taiwan; Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
⁶ Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei, 11031, Taiwan.
⁷ Core Facility Center, Office of Research and Development, Taipei Medical University, Taipei, 11031, Taiwan; Department of Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
⁸ Institute of Sociology, Academia Sinica, Taipei, 11529, Taiwan.
⁹ Department of Periodontology, School of Dentistry, National Defense Medical, Center and Tri-Service General Hospital, Taipei, 11490, Taiwan.
¹⁰ School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
¹¹ Taipei Cancer Center, Taipei Medical University, Taipei, 11031, Taiwan.
¹² Taipei Cancer Center, Taipei Medical University, Taipei, 11031, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, 11031, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
¹³ Taipei Cancer Center, Taipei Medical University, Taipei, 11031, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, 11031, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan; Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, 12208, USA. Electronic address: linhy@tmu.edu.tw.
¹⁴ Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, 12208, USA.
¹⁵ Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, 12208, USA; Albany Medical College, Albany, NY, 12208, USA.

PMID: 31336132
DOI: 10.1016/j.fct.2019.110693

Abstract

Thyroid hormone, L-thyroxine (T₄), induces inflammatory genes expressions and promotes cancer growth. It also induces expression of the checkpoint programmed death-ligand 1 (PD-L1), which plays a vital role in cancer progression. On the other hand, resveratrol inhibits inflammatory genes expressions. Moreover, resveratrol increases nuclear inducible cyclooxygenase (COX)-2 accumulation, complexes with p53, and induces p53-dependent anti-proliferation. In this study, we investigated the effect of T₄ on resveratrol-induced anti-proliferation in oral cancer. T₄ increased the expression and cytoplasmic accumulation of PD-L1. Increased expressions of pro-inflammatory genes, interleukin (IL)-1β and transforming growth factor (TGF)-β1, were shown to stimulate PD-L1 expression. T₄ stimulated pro-inflammatory and proliferative genes expressions, and oral cancer cells proliferation. In contrast, resveratrol inhibited those genes and activated anti-proliferative genes. T₄ retained resveratrol-induced COX-2 in cytoplasm and prevented COX-2 nuclear accumulation when resveratrol treated cancer cells. A specific signal transducer and activator of transcription 3 (STAT3) inhibitor, S31-201, blocked T₄-induced inhibition and restored resveratrol-induced nuclear COX-2 accumulation. By inhibiting the T₄-activated STAT3 signal transduction axis with S31-201, resveratrol was able to sequentially reestablish COX-2/p53-dependent gene expressions and anti-proliferation. These findings provide a novel understanding of the inhibitory effects of T₄ on resveratrol-induced anticancer properties via the sequential expression of PD-L1 and inflammatory genes.

Keywords: Inflammation; L-thyroxine; Oral cancer; PD-L1; Resveratrol.

MeSH terms

Cell Line, Tumor
Cell Nucleus / drug effects
Cell Nucleus / enzymology
Cell Proliferation / drug effects*
Cyclooxygenase 2 / metabolism
Cytokines / genetics*
Gene Expression / drug effects*
Humans
Inflammation Mediators / metabolism*
Mouth Neoplasms / metabolism
Mouth Neoplasms / pathology*
Resveratrol / pharmacology*
STAT3 Transcription Factor / metabolism
Thyroxine / pharmacology*

Substances

Cytokines
Inflammation Mediators
STAT3 Transcription Factor
STAT3 protein, human
Cyclooxygenase 2
Resveratrol
Thyroxine