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Inhibition of c-Jun N-terminal kinase activity enhances vestibular schwannoma cell sensitivity to gamma irradiation.

ABSTRACT: Radiosurgery is increasingly used to treat vestibular schwannomas (VSs). Increasing the sensitivity of VS cells to irradiation (IR) could allow for lower and/or more effective doses of IR, improving safety and efficacy. Persistent c-Jun N-terminal kinase (JNK) activity in VS cells reduces cell death by suppressing the accumulation of reactive oxygen species (ROS), raising the possibility that JNK activity protects against IR-induced VS cell death, which is mediated by ROS.To determine the extent to which JNK signaling contributes to VS cell radiosensitivity.Primary human VS cultures, derived from acutely resected tumors, received single doses (5-40 Gy) of gamma irradiation. Histone 2AX phosphorylation, a marker of IR-induced DNA damage, was assayed by Western blot and immunostaining. ROS levels were quantified by measuring 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) fluorescence. Cell apoptosis was determined by terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling.The JNK inhibitors SP6000125 and I-JIP reduced histone 2AX phosphorylation after IR. They also increased H2DCFDA fluorescence in nonirradiated cultures and significantly increased IR-induced (5-10 Gy) H2DCFDA fluorescence 72 hours, but not 2 hours, after IR. Finally, I-JIP (50 ?mol/L) significantly increased VS cell apoptosis in cultures treated with 20 to 40 Gy. I-JIP (20 ?mol/L), SP600125 (20 ?mol/L), and JNK1/2 short interfering RNA knockdown each increased VS cell apoptosis in cultures treated with 30 to 40 Gy, but not lower doses, of IR.Inhibition of JNK signaling decreases histone 2AX phosphorylation and increases ROS and apoptosis in VS cells after gamma irradiation. These results raise the possibility of using JNK inhibitors to increase the effectiveness of radiosurgery for treatment of VSs.

SUBMITTER: Yue WY

PROVIDER: S-EPMC4313352 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Inhibition of c-Jun N-terminal kinase activity enhances vestibular schwannoma cell sensitivity to gamma irradiation.

Yue Wei Ying WY Clark J Jason JJ Telisak Michael M Hansen Marlan R MR

Neurosurgery 20130901 3

<h4>Background</h4>Radiosurgery is increasingly used to treat vestibular schwannomas (VSs). Increasing the sensitivity of VS cells to irradiation (IR) could allow for lower and/or more effective doses of IR, improving safety and efficacy. Persistent c-Jun N-terminal kinase (JNK) activity in VS cells reduces cell death by suppressing the accumulation of reactive oxygen species (ROS), raising the possibility that JNK activity protects against IR-induced VS cell death, which is mediated by ROS.<h4> ...[more]

PMID: 23728448

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Project description:BackgroundThe clinical features and therapeutic measures of vestibular schwannoma (VS) radiation-related aneurysm (RRA) have not been well described. We reported the first VS RRA case admitted for acute anterior inferior cerebella artery (AICA) ischemic symptoms. Literature was reviewed to present the research fruits about VS RRAs, and some therapeutic advices were given.Materials and methodsA 54-year-old woman who had undergone GKS 10 years previously for a right VS was admitted to our hospital in 2018 because of sudden onset of severe vertigo and vomiting, accompanied with unsteady gait. During tumor resection, a dissecting aneurysm arose from the main trunk of AICA was encountered accidently within the tumor. The aneurysm was successfully treated with direct clip ligation, sparing the parent vessel. Data about this case were combined with those of other 11 radiation-related AICA aneurysm cases retrieved from the current literature. The following parameters were evaluated: Age, Sex, Diagnostic method, Location of aneurysm, Age of radiotherapy (Years)/Latency, Rupture, x-ray dosage, Type of radiotherapy, History of surgical resection of VS, Aneurysm Type, Morphology, Number, Treatment, Operative complications, Sequela, Outcome. VS RRAs mainly occurred in women (75%) with a median age of 62.5 years and were mainly located on AICA. Ruptured aneurysms accounted for 75.0% of the total cases. This paper reported the first VS case admitted with acute AICA ischemic symptoms. Cases with sacciform-like, irregular and fusiform-shaped aneurysms accounted for 50.0%, 25.0% and 25.0% of the total, respectively. After surgical treatment, 75.0% patients recovered, except for 3 patients who developed new ischemic consequence.ConclusionPatients should be informed of the risk of RRAs after receiving radiotherapy for VS. In these patients, RRAs should be suspected when subarachnoid hemorrhage or AICA ischemic symptoms occurred. Active intervention should be conducted considering the high instability and bleeding rate of VS RRAs.

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Inhibition of c-Jun N-terminal kinase activity enhances vestibular schwannoma cell sensitivity to gamma irradiation.

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Inhibition of c-Jun N-terminal kinase activity enhances vestibular schwannoma cell sensitivity to gamma irradiation.

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