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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Article number110693
JournalFood and Chemical Toxicology
Volume132
DOIs
Publication statusPublished - Oct 1 2019

Fingerprint

L-thyroxine
Mouth Neoplasms
resveratrol
thyroid hormones
Thyroid Hormones
cytokines
Cells
Cytokines
prostaglandin synthase
Cyclooxygenase 2
Gene expression
Genes
death
Ligands
Gene Expression
STAT3 Transcription Factor
gene expression
genes
transcription (genetics)
neoplasm cells

Keywords

  • Inflammation
  • L-thyroxine
  • Oral cancer
  • PD-L1
  • Resveratrol

ASJC Scopus subject areas

  • Food Science
  • Toxicology

Cite this

Thyroid hormone-induced expression of inflammatory cytokines interfere with resveratrol-induced anti-proliferation of oral cancer cells. / Chen, Yi Ru; Chen, Yu Shen; Chin, Yu Tang; Li, Zi Lin; Shih, Ya Jung; Yang, Yu Chen S.H.; ChangOu, Chun A.; Su, Po Yu; Wang, Shwu Huey; Wu, Yun Hsuan; Chiu, Hsien Chung; Lee, Sheng Yang; Liu, Leroy F.; Whang-Peng, Jacqueline; Lin, Hung Yun; Mousa, Shaker A.; Davis, Paul J.; Wang, Kuan.

In: Food and Chemical Toxicology, Vol. 132, 110693, 01.10.2019.

Research output: Contribution to journalArticle

Chen, Yi Ru ; Chen, Yu Shen ; Chin, Yu Tang ; Li, Zi Lin ; Shih, Ya Jung ; Yang, Yu Chen S.H. ; ChangOu, Chun A. ; Su, Po Yu ; Wang, Shwu Huey ; Wu, Yun Hsuan ; Chiu, Hsien Chung ; Lee, Sheng Yang ; Liu, Leroy F. ; Whang-Peng, Jacqueline ; Lin, Hung Yun ; Mousa, Shaker A. ; Davis, Paul J. ; Wang, Kuan. / Thyroid hormone-induced expression of inflammatory cytokines interfere with resveratrol-induced anti-proliferation of oral cancer cells. In: Food and Chemical Toxicology. 2019 ; Vol. 132.
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AU - Chen, Yu Shen

AU - Chin, Yu Tang

AU - Li, Zi Lin

AU - Shih, Ya Jung

AU - Yang, Yu Chen S.H.

AU - ChangOu, Chun A.

AU - Su, Po Yu

AU - Wang, Shwu Huey

AU - Wu, Yun Hsuan

AU - Chiu, Hsien Chung

AU - Lee, Sheng Yang

AU - Liu, Leroy F.

AU - Whang-Peng, Jacqueline

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AU - Wang, Kuan

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AB - 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.

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