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

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

Author information

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.

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

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

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