title: 14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2.
abstract: 14-3-3σ has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3σ contributes to these resistances via inhibiting apoptosis and arresting cells in G2-M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3σ causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2-M phase following DNA-damaging treatments. We showed that 14-3-3σ contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2-M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSB). The increased NHEJ repair activity was due to 14-3-3σ-mediated upregulation of PARP1 expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the other hand, the increased G2-M arrest following IR was due to 14-3-3σ-induced Chk2 expression.Implications:These findings reveal an important molecular basis of 14-3-3σ function in cancer cell resistance to chemo/radiation therapy and in poor prognosis of human cancers.Mol Cancer Res; 15(4); 418-28. ©2017 AACR.
authors.affiliation: Departments of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.|Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.|Guangdong Esophageal Cancer Institute, Guangzhou, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Departments of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Zizheng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Departments of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Jenny
authors.initials: J
authors.lastname: Beebe
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China. jianzhan@iu.edu Fulw@mail.sysu.edu.cn.|Guangdong Esophageal Cancer Institute, Guangzhou, China.
authors.forename: Liwu
authors.initials: L
authors.lastname: Fu
authors.affiliation: Departments of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana. jianzhan@iu.edu Fulw@mail.sysu.edu.cn.
authors.forename: Jian-Ting
authors.initials: JT
authors.lastname: Zhang
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000235:genetics* / Q000378:metabolism; D059766:DNA End-Joining Repair; D019008:Drug Resistance, Neoplasm; D005095:Exoribonucleases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000532:radiotherapy; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics* / Q000378:metabolism; D011836:Radiation Tolerance; D015854:Up-Regulation
chemical_list: D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D005095:Exoribonucleases; C413442:SFN protein, human