Phthalates promote the invasion of hepatocellular carcinoma cells by enhancing the interaction between Pregnane X receptor and E26 transformation specific sequence 1.

Abstract

Phthalates (PAEs) are considered endocrine-disrupting chemicals (EDCs), a series of compounds able to disrupt the normal regulation of the human endocrine-system. In the present study, we investigated the roles of four PAEs, butyl benzyl phthalate (BBP), dibutyl phthalate (DBP), dimethyl phthalate (DMP), and diethyl phthalate (DEP), in hepatocellular carcinoma (HCC) cells. We define novel roles for the PAEs on the migration of HCC cells via their enhancing of the interaction between the pregnane X receptor (PXR) and E26 transformation specific sequence 1 (ETS-1). Our results indicate that PAEs induced the transcriptional activation of ETS-1 and PXR. PXR activated by PAEs could bind to ETS-1 directly and enhanced the activity of ETS-1, which resulted in the induction of invasion-related ETS-1 target genes. The "LXXLL" motif in the ETS-1C-terminal was essential for the interaction between PXR and ETS-1 induced by PAEs. Treatment of PAEs promoted the nuclear accumulation of ETS-1 or the recruitment of ETS-1, but not in cells expressing ETS-1 with a mutated LXXLL motif in its downstream gene promoter region, or following transfection of PXR siRNA. Treatment with the PXR antagonist ketoconazole almost completely inhibited the effects of PAEs. Moreover, PAEs enhanced the in vitro or in vivo invasion of HCC cells via PXR/ETS-1. Therefore, our results not only contribute to a better understanding of HCC, but also extended the roles of EDCs regulating human malignancies.

• Authors: Yabing Du, Xiaoyi Shi, Wang Ma, Peihao Wen, Pu Yu, Xin Wang, Pengli Fang, Aixia Chen, Zhiqiang Gao, Kang Cui
• Journal: Pharmacological research (Pharmacol Res) Vol. 169 Pg. 105648 (07 2021) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 33965509 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• ETS1 protein, human
• Endocrine Disruptors
• NR1I2 protein, human
• Phthalic Acids
• Pregnane X Receptor
• Proto-Oncogene Protein c-ets-1
• dimethyl phthalate
• Dibutyl Phthalate
• diethyl phthalate
• butylbenzyl phthalate

Topics

• Animals
• Blotting, Western
• Carcinoma, Hepatocellular (chemically induced, metabolism, pathology)
• Cell Line, Tumor
• Dibutyl Phthalate (pharmacology)
• Endocrine Disruptors (pharmacology)
• HEK293 Cells (drug effects)
• Humans
• Immunoprecipitation
• Liver Neoplasms (chemically induced, metabolism, pathology)
• Mice
• Mice, Nude
• Molecular Docking Simulation
• Neoplasm Invasiveness (pathology)
• Neoplasm Transplantation
• Phthalic Acids (pharmacology)
• Polymerase Chain Reaction
• Pregnane X Receptor (drug effects, metabolism)
• Proto-Oncogene Protein c-ets-1 (drug effects, metabolism)