Regulation of autophagy via PERK-eIF2α effectively relieve the radiation myelitis induced by iodine-125.

Abstract

Radiation myelitis is the most serious complication in clinical radiotherapy for spinal metastases. We previously showed that (125)I brachytherapy induced apoptosis of spinal cord neurons accompanied by autophagy. In this study, we further investigated the mechanism by which (125)I radiation triggered autophagy in neural cells. We found that autophagy induced by (125)I radiation was involved in endoplasmic reticulum (ER) stress and mainly dependent on PERK-eIF2α pathway. The expressions of LC3II, ATG12 and PI3K were significantly suppressed in PERK knockout neural cells. Meanwhile, the expressions of phosphorylated-Akt s473 and caspase3/8 all significantly increased in neural cells transfected with a PERK siRNA and which enhanced apoptosis of neurons after (125)I radiation. The results were consistent with that by MTT and Annexin-FITC/PT staining. In animal model of banna pigs with radiation myelitis caused by (125)I brachytherapy, we have successfully decreased PERK expression by intrathecal administration of the lentivirus vector. The apoptosis rate was significantly higher than that in control group and which deteriorated radiation myelitis of banna pigs. Thus, autophagy caused by (125)I radiation was mainly as an attempt of cell survival at an early stage, but it would be a self-destructive process and promoted the process of apoptosis and necrosis radiated by (125)I for more than 72 hours. The study would be useful and helpful to maximize efficiency of radiation therapy in clinical therapy.

• Authors: Zuozhang Yang, Yongqing Xu, Lei Xu, Giulio Maccauro, Barbara Rossi, Yanjin Chen, Hongjun Li, Jing Zhang, Hongpu Sun, Yihao Yang, Da Xu, Xuefeng Liu
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e76819 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24223705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Eukaryotic Initiation Factor-2
• Iodine Radioisotopes
• Radiopharmaceuticals
• Small Ubiquitin-Related Modifier Proteins
• Phosphatidylinositol 3-Kinases
• PERK kinase
• eIF-2 Kinase

Topics

• Animals
• Apoptosis
• Autophagy
• Brachytherapy
• Cell Proliferation
• Cell Survival (radiation effects)
• Cells, Cultured
• Endoplasmic Reticulum Stress
• Eukaryotic Initiation Factor-2 (physiology)
• Female
• Gene Knockdown Techniques
• Iodine Radioisotopes (adverse effects)
• Motor Activity (radiation effects)
• Myelitis (etiology, metabolism, pathology)
• Neurons (physiology, radiation effects)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Radiation Injuries, Experimental (etiology, metabolism, pathology)
• Radiopharmaceuticals (adverse effects)
• Rats
• Signal Transduction
• Small Ubiquitin-Related Modifier Proteins (genetics, metabolism)
• Spinal Cord (pathology)
• Swine
• Swine, Miniature
• Transcriptional Activation (radiation effects)
• eIF-2 Kinase (physiology)