The effect of chemotherapeutic agents on epidermal neural crest stem cells

Document Type : Original article

Authors

1 Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

2 Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases. Shahid Beheshti University of Medical Sciences, Tehran, Iran

3 Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

4 Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

5 Autophagy Research Center, Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

6 School of Public Health, University of Nevada, Las Vegas, NV 89154, USA

7 Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

Human Epidermal Neural Crest Stem Cells (hEPI-NCSCs), as a transient population of multipotent migratory stem cells can differentiate into multiple types of neural and non-neural cells and tissues in the body. Here, we tried to determine the role of chemo agents in mediating the stress induced pathways like autophagy and unfolded protein responses (UPR), as well as the migratory potential of NCSCs. hEPI-NCSCs were treated with chemo agents including Dithiothreitol [(DTT) 10µM)], Salinomycin (9mM), Ebselen (10mM), 5-Fluorouracil [(5-FU) 8µM] and Cisplatin (6mM) for 72 hours. The reverse transcription-quantitative polymerase chain reaction (RT- qPCR) and scratch wound healing assays were used to assess the effect of chemo agents on NCSCs function. After treatment with DTT, hEPI-NCSCs upregulated the expression of genes related to autophagy and UPR pathways including LC3, P62 and CHOP. These genes were also overexpressed when NCSCs were treated with Salinomycin. Reverse results were verified by 5-FU, Ebselen and Cisplatin treatment. Salinomycin and Cisplatin upregulated the expression of XBP-1, which down regulated with DTT, 5-FU and Ebselen. Inhibition in migratory capacity of NCSCs was detected following treatment by Salinomycin, 5-FU, Ebselen and Cisplatin. DTT and 5-FU promoted the expression of BDNF, while Salinomycin, Cisplatin and Ebselen treatment reduced its expression. During exposition to DTT, the autophagy pathway was activated, implying that autophagy functions as a survival mechanism for deactivating the inhibitory effects of DTT on the migratory capacity of NCSCs. Chemotherapeutic agents like 5-FU and cisplatin exert cytotoxic effects on NCSCs by suppressing autophagy, UPR pathways, and the migratory potential of NCSCs.

Keywords

References

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