title: PID1 increases chemotherapy-induced apoptosis in medulloblastoma and glioblastoma cells in a manner that involves NFκB.
abstract: Phosphotyrosine Interaction Domain containing 1 (PID1; NYGGF4) inhibits growth of medulloblastoma, glioblastoma and atypical teratoid rhabdoid tumor cell lines. PID1 tumor mRNA levels are highly correlated with longer survival in medulloblastoma and glioma patients, suggesting their tumors may have been more sensitive to therapy. We hypothesized that PID1 sensitizes brain tumors to therapy. We found that PID1 increased the apoptosis induced by cisplatin and etoposide in medulloblastoma and glioblastoma cell lines. PID1 siRNA diminished cisplatin-induced apoptosis, suggesting that PID1 is required for cisplatin-induced apoptosis. Etoposide and cisplatin increased NFκB promoter reporter activity and etoposide induced nuclear translocation of NFκB. Etoposide also increased PID1 promoter reporter activity, PID1 mRNA, and PID1 protein, which were diminished by NFκB inhibitors JSH-23 and Bay117082. However, while cisplatin increased PID1 mRNA, it decreased PID1 protein. This decrease in PID1 protein was mitigated by the proteasome inhibitor, bortezomib, suggesting that cisplatin induced proteasome dependent degradation of PID1. These data demonstrate for the first time that etoposide- and cisplatin-induced apoptosis in medulloblastoma and glioblastoma cell lines is mediated in part by PID1, involves NFκB, and may be regulated by proteasomal degradation. This suggests that PID1 may contribute to responsiveness to chemotherapy.
authors.affiliation: Saban Research Institute at Children's Hospital Los Angeles, Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, Los Angeles, California, 90027, USA.
authors.forename: Jingying
authors.initials: J
authors.lastname: Xu
authors.affiliation: Saban Research Institute at Children's Hospital Los Angeles, Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, Los Angeles, California, 90027, USA.
authors.forename: Xiuhai
authors.initials: X
authors.lastname: Ren
authors.affiliation: Saban Research Institute at Children's Hospital Los Angeles, Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, Los Angeles, California, 90027, USA.
authors.forename: Anup Singh
authors.initials: AS
authors.lastname: Pathania
authors.affiliation: Saban Research Institute at Children's Hospital Los Angeles, Cellular Imaging Core, Los Angeles, California, 90027, USA.
authors.forename: G Esteban
authors.initials: GE
authors.lastname: Fernandez
authors.affiliation: Saban Research Institute at Children's Hospital Los Angeles, Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, Los Angeles, California, 90027, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tran
authors.affiliation: Saban Research Institute at Children's Hospital Los Angeles, Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, Los Angeles, California, 90027, USA.
authors.forename: Yifu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Saban Research Institute at Children's Hospital Los Angeles, Department of Radiology, Los Angeles, California, 90027, USA.
authors.forename: Rex A
authors.initials: RA
authors.lastname: Moats
authors.affiliation: Saban Research Institute at Children's Hospital Los Angeles, Department of Radiology, Los Angeles, California, 90027, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Shackleford
authors.affiliation: Saban Research Institute at Children's Hospital Los Angeles, Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, Los Angeles, California, 90027, USA. epstein@usc.edu.|Keck School of Medicine, University of Southern California, Departments of Pediatrics and Pathology, Los Angeles, California, 90033, USA. epstein@usc.edu.
authors.forename: Anat
authors.identifier: http://orcid.org/0000-0003-4269-4373
authors.initials: A
authors.lastname: Erdreich-Epstein
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005909:Glioblastoma / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D016328:NF-kappa B; C514653:PID1 protein, human; D005047:Etoposide; D002945:Cisplatin