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 125I brachytherapy induced apoptosis of spinal cord neurons accompanied by autophagy. In this study, we further investigated the mechanism by which 125I radiation triggered autophagy in neural cells. We found that autophagy induced by 125I 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 125I radiation. The results were consistent with that by MTT and Annexin-FITC/PT staining. In annimal model of banna pigs with radiation myelitis caused by 125I 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 125I 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 125I for more than 72 hours. The study would be useful and helpful to maximize efficiency of radiation therapy in clinical therapy.

Role of PERK‐eIF2α signaling pathway in fetal male rats with hypospadias induced by di‐n‐butyl phthalate

“…Furthermore, the GT fibroblast of fetal rat was isolated to perform in‐vitro transfection experiments, and the downregulated PERK‐eIF2α signaling pathway, eIF2α phosphorylation and ATF4 expression, and increased cell apoptosis, as well as reduced ratio of LC3‐II/LC3‐I and increased P62 were detected after PERK silencing, implying that cell autophagy was restricted but apoptosis was enhanced through inhibition of PERK‐eIF2α signaling pathway. In radiation myelitis induced by Iodine‐125, the expressions of LC3II and ATG12 were also significantly declined with increased cell apoptosis in neural cells when transfected with a PERK siRNA [35], which was in agreement with our findings. Therefore, PERK silencing reduced the conversion of LC3‐I to LC3‐II and inhibited cell autophagy via alleviation of eIF2α phosphorylation and ATF4 expression, thereby facilitating the cell survival and influencing the development of hypospadias.…”

PERK-Mediated Unfolded Protein Response Signaling Restricts Replication of the Tick-Borne Flavivirus Langat Virus

“…Activated PERK phosphorylates eIF2α, which rapidly inhibits protein synthesis, and can lead to CHOP-mediated apoptosis. PERK also engages the autophagic system via LC3 lipidation, a key element in autophagy [50,56]. PERK signaling has been demonstrated to inhibit several mosquito-borne flaviviruses, including DENV, WNV, and WNV KUN [25][26][27].…”

“…Published studies have also linked PERK activation to autophagic regulation [50][51][52]. Autophagy has varied and apparently contradictory effects on flavivirus replication [35].…”

Crosstalk between autophagy and intracellular radiation response (Review)

“…Although the main signaling pathway of ER stress that is activated following irradiation is still a debatable one; some recent evidence suggests that PERK-eIF2a and/or IRE1a may serve as the main executing pathways of ER stress in irradiation scenarios (80)(81)(82). A link between autophagy and the ER stress has been further substantiated by the PERKeIF2α pathway which is essential for autophagy induction after ER stress.…”