Soichiro Nishioka1,2, Ping-Hsiu Wu2, Toshiaki Yakabe3, Amato J Giaccia4, Quynh-Thu Le4, Hidefumi Aoyama5, Shinichi Shimizu2,6, Hiroki Shirato2, Yasuhito Onodera2,7, Jin-Min Nam2. 1. Molecular and Cellular Dynamics Research, Graduate School of Biomedical Science and Engineering, Hokkaido University, Sapporo, Japan. 2. Global Center for Biomedical Science and Engineering, Faculty of Medicine, Hokkaido University, Sapporo, Japan. 3. School of Medicine, Hokkaido University, Sapporo, Japan. 4. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA. 5. Department of Radiation Oncology, Faculty of Medicine, Hokkaido University, Sapporo, Japan. 6. Department of Radiation Medical Science and Engineering, Faculty of Medicine, Hokkaido University, Sapporo, Japan. 7. Department of Molecular Biology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
Abstract
BACKGROUND: Radiotherapy is the standard treatment for glioblastoma (GBM). However, radioresistance of GBM cells leads to recurrence and poor patient prognosis. Recent studies suggest that secretion factors have important roles in radioresistance of tumor cells. This study aims to determine whether Rab27b, a small GTPase involved in secretory vesicle trafficking, plays a role in radioresistance of GBM. METHODS: Microarray analysis, cell viability analysis, apoptosis assay, immunostaining, and in vivo experiments were performed to assess the effect of Rab27b on radioresistance of GBM. We further investigated paracrine effects mediated by Rab27b after X-ray irradiation using coculture systems of glioma cell lines. RESULTS: Rab27b was specifically upregulated in irradiated U87MG cells. Furthermore, Rab27b knockdown decreased the proliferation of GBM cells after irradiation. Knockdown of Rab27b in U87MG cells combined with radiation treatment suppressed orthotopic tumor growth in the mouse brain and prolonged the survival of recipient mice. Interestingly, the co-upregulation of Rab27b and epiregulin (EREG), a member of the epidermal growth factor (EGF) family, correlated with radioresistance in glioma cell lines. Additionally, EREG, which was secreted from U87MG cells via Rab27b-mediated mechanism, activated EGF receptor and contributed to H4 cell proliferation in a paracrine manner. CONCLUSIONS: Our results show that Rab27b mediates the radioresistance of highly malignant GBM cells. Rab27b promotes the proliferation of adjacent cells through EREG-mediated paracrine signaling after irradiation. Thus, the Rab27b-EREG pathway is a novel potential target to improve the efficacy of radiotherapy in GBM.
BACKGROUND: Radiotherapy is the standard treatment for glioblastoma (GBM). However, radioresistance of GBM cells leads to recurrence and poor patient prognosis. Recent studies suggest that secretion factors have important roles in radioresistance of tumor cells. This study aims to determine whether Rab27b, a small GTPase involved in secretory vesicle trafficking, plays a role in radioresistance of GBM. METHODS: Microarray analysis, cell viability analysis, apoptosis assay, immunostaining, and in vivo experiments were performed to assess the effect of Rab27b on radioresistance of GBM. We further investigated paracrine effects mediated by Rab27b after X-ray irradiation using coculture systems of glioma cell lines. RESULTS: Rab27b was specifically upregulated in irradiated U87MG cells. Furthermore, Rab27b knockdown decreased the proliferation of GBM cells after irradiation. Knockdown of Rab27b in U87MG cells combined with radiation treatment suppressed orthotopic tumor growth in the mouse brain and prolonged the survival of recipient mice. Interestingly, the co-upregulation of Rab27b and epiregulin (EREG), a member of the epidermal growth factor (EGF) family, correlated with radioresistance in glioma cell lines. Additionally, EREG, which was secreted from U87MG cells via Rab27b-mediated mechanism, activated EGF receptor and contributed to H4 cell proliferation in a paracrine manner. CONCLUSIONS: Our results show that Rab27b mediates the radioresistance of highly malignant GBM cells. Rab27b promotes the proliferation of adjacent cells through EREG-mediated paracrine signaling after irradiation. Thus, the Rab27b-EREG pathway is a novel potential target to improve the efficacy of radiotherapy in GBM.
Authors: Jin-Min Nam; Kazi M Ahmed; Sylvain Costes; Hui Zhang; Yasuhito Onodera; Adam B Olshen; Kanako C Hatanaka; Rumiko Kinoshita; Masayori Ishikawa; Hisataka Sabe; Hiroki Shirato; Catherine C Park Journal: Breast Cancer Res Date: 2013 Impact factor: 6.466
Authors: Anna B Meier; Sarala Raj Murthi; Hilansi Rawat; Christopher N Toepfer; Gianluca Santamaria; Manuel Schmid; Elisa Mastantuono; Thomas Schwarzmayr; Riccardo Berutti; Julie Cleuziou; Peter Ewert; Agnes Görlach; Karin Klingel; Karl-Ludwig Laugwitz; Christine E Seidman; Jonathan G Seidman; Alessandra Moretti; Cordula M Wolf Journal: iScience Date: 2021-12-09