Nerve growth factor prevents arsenic-induced toxicity in PC12 cells through the AKT/GSK-3β/NFAT pathway.

Abstract

The potential risk of arsenic-related neurodegeneration has been a growing concern. Arsenic exposure has been reported to disrupt neurite growth and neuron body integrity in vitro; however, its underlying mechanism remains unclear. Previously, we showed that arsenic sulfide (AS) exerted cytotoxicity in gastric and colon cancer cells through regulating nuclear factor of the activated T cells (NFAT) pathway. The NFAT pathway regulates axon path finding and neural development. Using neural crest cell line PC12 cells as a model, here we show that AS caused mitochondrial membrane potential collapse, reactive oxygen species production, and cytochrome c release, leading to mitochondria-mediated apoptosis via the AKT/GSK-3β/NFAT pathway. Increased glycogen synthase kinase-3 beta (GSK-3β) activation leads to the inactivation of NFAT and its antiapoptotic effects. Through inhibiting GSK-3β activity, both nerve growth factor (NGF) and Tideglusib, a GSK-3β inhibitor partially rescued the PC12 cells from the AS-induced cytotoxicity and restored the expression of NFATc3. In addition, overexpression of NFATc3 stimulated neurite outgrowth and potentiated the effect of NGF on promoting the neurite outgrowth. Collectively, our results show that NFATc3 serves as the downstream target of NGF and plays a key role in preventing AS-induced neurotoxicity through regulating the AKT/GSK-3β/NFAT pathway in PC12 cells.

• Authors: Zhen Tan, Ting Kang, Xiuli Zhang, Yingying Tong, Siyu Chen
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 234 Issue 4 Pg. 4726-4738 (04 2019) ISSN: 1097-4652 [Electronic] United States
• PMID: 30256405 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Wiley Periodicals, Inc.

Chemical References

• Arsenicals
• NFATC Transcription Factors
• Neuroprotective Agents
• Sulfides
• arsenic trisulfide
• Nerve Growth Factor
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (drug effects)
• Arsenic Poisoning (enzymology, pathology, prevention & control)
• Arsenicals
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Glycogen Synthase Kinase 3 beta (metabolism)
• Mitochondria (drug effects, metabolism, pathology)
• NFATC Transcription Factors (metabolism)
• Nerve Growth Factor (pharmacology)
• Neurons (drug effects, enzymology, pathology)
• Neuroprotective Agents (pharmacology)
• PC12 Cells
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Signal Transduction
• Sulfides (toxicity)
• Time Factors