title: Inhibition of the Rac1-WAVE2-Arp2/3 signaling pathway promotes radiosensitivity via downregulation of cofilin-1 in U251 human glioma cells.
abstract: The Ras-related C3 botulinum toxin substrate 1 (Rac1)-WASP-family verprolin-homologous protein-2 (WAVE2)-actin-related protein 2/3 (Arp2/3) signaling pathway has been identified to be involved in cell migration and invasion in various types of cancer cell. Cofilin‑1 (CFL‑1), which is regulated by the Rac1‑WAVE2‑Arp2/3 signaling pathway, may promote radioresistance in glioma. Therefore, the present study aimed to investigate the potential role of the Rac1‑WAVE2‑Arp2/3 signaling pathway in radioresistance in U251 human glioma cells and elucidate its affect on CFL‑1 expression. Western blot analysis was performed to evaluate the protein expression of CFL‑1. In the present study, Rac1 was inhibited by NSC 23766, WAVE2 was inhibited by transfection with short hairpin (sh)RNA‑WAVE2 using Lipofectamine™ 2000 and Arp2/3 was inhibited by CK‑666. Cell viability was measured using the 3‑(4,5‑dimethylthiazol‑2‑yl)-2,5‑diphenyltetrazolium bromide assay, the cell migration ability was examined by a wound‑healing assay, and the cell invasion ability was assessed using a Transwell culture chamber system. The results showed that inhibition of the Rac1‑WAVE2‑Arp2/3 signaling pathway using NSC 23766, shRNA‑WAVE2 or CK‑666 reduced the cell viability, migration and invasion abilities in U251 human glioma cells, concordant with a reduced expression of CFL‑1. Furthermore, the expression of CFL‑1 was significantly increased in radioresistant U251 glioma cells when compared with normal U251 human glioma cells. These findings indicate that inhibition of the Rac1‑WAVE2‑Arp2/3 signaling pathway may promote radiosensitivity, which may partially result from the downregulation of CFL‑1 in U251 human glioma cells.
authors.affiliation: Department of Neurosurgery, Nanjing Medical University, Affiliated Nanjing Brain Hospital, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Nanjing Medical University, Affiliated Nanjing Brain Hospital, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Chen-Han
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Nanjing Medical University, Affiliated Nanjing Brain Hospital, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, Nanjing Medical University, Affiliated Nanjing Brain Hospital, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Nanjing Medical University, Affiliated Nanjing Brain Hospital, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Jin-Bing
authors.initials: JB
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Nanjing Medical University, Affiliated Nanjing Brain Hospital, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Chun-Fa
authors.initials: CF
authors.lastname: Qian
authors.affiliation: Neuropsychiatric Institute, Nanjing Medical University, Affiliated Nanjing Brain Hospital, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Neurosurgery, Nanjing Medical University, Affiliated Nanjing Brain Hospital, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Liu
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D051338:Cofilin 1 / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation / Q000528:radiation effects*; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000096:biosynthesis* / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051376:Actin-Related Protein 2-3 Complex; C495810:CFL1 protein, human; D051338:Cofilin 1; D009363:Neoplasm Proteins; C107953:RAC1 protein, human; C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D020830:rac1 GTP-Binding Protein