Quinotrierixin inhibits proliferation of human retinal pigment epithelial cells.

Abstract

PURPOSE:

To investigate the effect of quinotrierixin, a previously reported inhibitor of X-box binding protein 1 (XBP1), on cell proliferation and viability in human retinal pigment epithelium (RPE) cells.

METHODS:

Subconfluent human RPE cells (ARPE-19) were exposed to quinotrierixin for 16-24 h. Cell proliferation was determined with 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay, hemocytometer counts, and CyQUANT NF Cell Proliferation Assay. Apoptosis was detected with terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling assay. XBP1 mRNA splicing and expression of endoplasmic reticulum stress response genes were determined in cells exposed to thapsigargin in the presence or absence of quinotrierixin. Overexpression of spliced XBP1 was achieved with adenovirus.

RESULTS:

Quinotrierixin reduced RPE cell proliferation in a dose-dependent manner without inducing apoptosis. In cells exposed to thapsigargin, quinotrierixin inhibited XBP1 mRNA splicing and PKR-like endoplasmic reticulum kinase activation, and reduced cellular and nuclear levels of spliced XBP1 and C/EBP homologous protein. Paradoxically, quinotrierixin exacerbated endoplasmic reticulum stress-induced phosphorylation of eIF2α, which in turn led to decreased protein translation. Overexpressing spliced XBP1 partially reversed the inhibition of cell proliferation by quinotrierixin. These results suggest that inhibiting XBP1 splicing contributes to quinotrierixin's negative effect on RPE cell proliferation, but other mechanisms such as reduction of protein translation are also involved.

CONCLUSIONS:

Quinotrierixin inhibits RPE cell proliferation and may be used as a novel antiproliferative drug for treating proliferative vitreoretinopathy. Future studies are needed to investigate the in vivo effect of quinotrierixin on RPE proliferation in animal models of proliferative vitreoretinopathy.

• Authors: Chen Chen, Joshua J Wang, Jingming Li, Qiang Yu, Sarah X Zhang
• Journal: Molecular vision (Mol Vis) Vol. 19 Pg. 39-46 ( 2013) ISSN: 1090-0535 [Electronic] United States
• PMID: 23335849 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DDIT3 protein, human
• DNA-Binding Proteins
• Regulatory Factor X Transcription Factors
• Transcription Factors
• X-Box Binding Protein 1
• XBP1 protein, human
• quinotrierixin
• Transcription Factor CHOP
• Rifabutin
• Thapsigargin
• EIF2AK3 protein, human
• eIF-2 Kinase

Topics

• Apoptosis (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA-Binding Proteins (antagonists & inhibitors, genetics)
• Endoplasmic Reticulum Stress (drug effects)
• Epithelial Cells (cytology, drug effects, metabolism)
• Humans
• RNA Splicing (drug effects)
• Regulatory Factor X Transcription Factors
• Retinal Pigment Epithelium (cytology, drug effects, metabolism)
• Rifabutin (analogs & derivatives, pharmacology)
• Thapsigargin (pharmacology)
• Transcription Factor CHOP (metabolism)
• Transcription Factors (antagonists & inhibitors, genetics)
• Vitreoretinopathy, Proliferative (drug therapy)
• X-Box Binding Protein 1
• eIF-2 Kinase (metabolism)