Cytoplasmic aryl hydrocarbon receptor regulates glycogen synthase kinase 3 beta, accelerates vimentin degradation, and suppresses epithelial–mesenchymal transition in non-small cell lung cancer cells

Ching Hao Li, Chen Wei Liu, Chi Hao Tsai, Yi Jen Peng, Yu Hsuan Yang, Po Lin Liao, Chen Chen Lee, Yu Wen Cheng, Jaw Jou Kang

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, has been studied extensively in carcinogenesis through the genomic pathway. In recent years, AHR has also been reported to exert positive or negative effects on epithelial–mesenchymal transition (EMT), the crucial step in tumor malignant progression. However, the detailed mechanism remains controversial. Analysis of AHR-expression levels in non-small cell lung cancer cell lines and lung cancer tissues revealed an inverse correlation between AHR protein levels and tumor cell invasion and metastasis. Overexpression of wild-type AHR in H1299 cells (AHR poorly expressed, potently invasive) not only accelerated mesenchymal vimentin degradation, but also prevented cell invasion in vitro and in vivo. In the absence of AHR agonists, the overexpressed AHR protein was predominantly localized in the cytoplasm, where it interacted with vimentin and functioned as an E3 ubiquitin ligase. A 6-h incubation with the proteasome inhibitor MG-132 fully rescued vimentin from AHR-mediated proteasomal degradation. In AHR-overexpressing H1299 cells, either vimentin degradation or invasive suppression could be reversed when glycogen synthase kinase 3 beta (GSK3β) was inactivated by CHIR-99021 treatment. In contrast, silencing of AHR in A549 cells (AHR highly expressed, weakly invasive) resulted in the downregulation of epithelial biomarkers (E-cadherin and claudin-1), augmentation of mesenchymal vimentin level, and GSK3β Ser-9 hyper-phosphorylation, which led to enhanced invasiveness. This work demonstrates that cytoplasmic, resting AHR protein may act as an EMT suppressor via a non-genomic pathway. Depletion of cytoplasmic AHR content represents a potential switch for EMT, thereby leading to the scattering of tumor cells.

Original languageEnglish
Pages (from-to)2165-2178
Number of pages14
JournalArchives of Toxicology
Volume91
Issue number5
DOIs
Publication statusPublished - May 1 2017

Fingerprint

Glycogen Synthase Kinase 3
Aryl Hydrocarbon Receptors
Vimentin
Non-Small Cell Lung Carcinoma
Cells
Degradation
Tumors
Cadherins
Glycogen Synthase Kinase 3 beta
Claudin-1
Neoplasms
Phosphorylation
Proteins
Proteasome Inhibitors
Ubiquitin-Protein Ligases
Biomarkers

Keywords

  • Aryl hydrocarbon receptor
  • Epithelial–mesenchymal transition
  • Glycogen synthase kinase 3 beta
  • Ubiquitin
  • Vimentin

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Cytoplasmic aryl hydrocarbon receptor regulates glycogen synthase kinase 3 beta, accelerates vimentin degradation, and suppresses epithelial–mesenchymal transition in non-small cell lung cancer cells. / Li, Ching Hao; Liu, Chen Wei; Tsai, Chi Hao; Peng, Yi Jen; Yang, Yu Hsuan; Liao, Po Lin; Lee, Chen Chen; Cheng, Yu Wen; Kang, Jaw Jou.

In: Archives of Toxicology, Vol. 91, No. 5, 01.05.2017, p. 2165-2178.

Research output: Contribution to journalArticle

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abstract = "Aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, has been studied extensively in carcinogenesis through the genomic pathway. In recent years, AHR has also been reported to exert positive or negative effects on epithelial–mesenchymal transition (EMT), the crucial step in tumor malignant progression. However, the detailed mechanism remains controversial. Analysis of AHR-expression levels in non-small cell lung cancer cell lines and lung cancer tissues revealed an inverse correlation between AHR protein levels and tumor cell invasion and metastasis. Overexpression of wild-type AHR in H1299 cells (AHR poorly expressed, potently invasive) not only accelerated mesenchymal vimentin degradation, but also prevented cell invasion in vitro and in vivo. In the absence of AHR agonists, the overexpressed AHR protein was predominantly localized in the cytoplasm, where it interacted with vimentin and functioned as an E3 ubiquitin ligase. A 6-h incubation with the proteasome inhibitor MG-132 fully rescued vimentin from AHR-mediated proteasomal degradation. In AHR-overexpressing H1299 cells, either vimentin degradation or invasive suppression could be reversed when glycogen synthase kinase 3 beta (GSK3β) was inactivated by CHIR-99021 treatment. In contrast, silencing of AHR in A549 cells (AHR highly expressed, weakly invasive) resulted in the downregulation of epithelial biomarkers (E-cadherin and claudin-1), augmentation of mesenchymal vimentin level, and GSK3β Ser-9 hyper-phosphorylation, which led to enhanced invasiveness. This work demonstrates that cytoplasmic, resting AHR protein may act as an EMT suppressor via a non-genomic pathway. Depletion of cytoplasmic AHR content represents a potential switch for EMT, thereby leading to the scattering of tumor cells.",
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AU - Tsai, Chi Hao

AU - Peng, Yi Jen

AU - Yang, Yu Hsuan

AU - Liao, Po Lin

AU - Lee, Chen Chen

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