title: RAD18 mediates resistance to ionizing radiation in human glioma cells.
abstract: Radioresistance remains a major challenge in the treatment of glioblastoma multiforme (GBM). RAD18 a central regulator of translesion DNA synthesis (TLS), has been shown to play an important role in regulating genomic stability and DNA damage response. In the present study, we investigate the relationship between RAD18 and resistance to ionizing radiation (IR) and examined the expression levels of RAD18 in primary and recurrent GBM specimens. Our results showed that RAD18 is an important mediator of the IR-induced resistance in GBM. The expression level of RAD18 in glioma cells correlates with their resistance to IR. Ectopic expression of RAD18 in RAD18-low A172 glioma cells confers significant resistance to IR treatment. Conversely, depletion of endogenous RAD18 in RAD18-high glioma cells sensitized these cells to IR treatment. Moreover, RAD18 overexpression confers resistance to IR-mediated apoptosis in RAD18-low A172 glioma cells, whereas cells deficient in RAD18 exhibit increased apoptosis induced by IR. Furthermore, knockdown of RAD18 in RAD18-high glioma cells disrupts HR-mediated repair, resulting in increased accumulation of DSB. In addition, clinical data indicated that RAD18 was significantly higher in recurrent GBM samples that were exposed to IR compared with the corresponding primary GBM samples. Collectively, our findings reveal that RAD18 may serve as a key mediator of the IR response and may function as a potential target for circumventing IR resistance in human GBM.
authors: Department of Minimally Invasive Neurosurgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors: Chen
authors: C
authors: Xie
authors: Department of Minimally Invasive Neurosurgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors: Hongwei
authors: H
authors: Wang
authors: Department of Minimally Invasive Neurosurgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors: Hongbin
authors: H
authors: Cheng
authors: Department of Minimally Invasive Neurosurgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors: Jianhua
authors: J
authors: Li
authors: Department of Minimally Invasive Neurosurgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Electronic address: drzwang@gmail.com.
authors: Zhi
authors: Z
authors: Wang
authors: Department of Minimally Invasive Neurosurgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Electronic address: drwuyue@gmail.com.
authors: Wu
authors: W
authors: Yue
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases
chemical_list: D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C485954:RAD18 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Glioblastoma multiforme; RAD18; Radioresistance; Translesion DNA synthesis