TY - JOUR
T1 - IFN‑β sensitizes TRAIL‑induced apoptosis by upregulation of death receptor 5 in malignant glioma cells
AU - Yoshimura, Sodai
AU - Sano, Emiko
AU - Hanashima, Yuya
AU - Yamamuro, Shun
AU - Sumi, Koichiro
AU - Ueda, Takuya
AU - Nakayama, Tomohiro
AU - Hara, Hiroyuki
AU - Yoshino, Atsuo
AU - Katayama, Yoichi
N1 - Funding Information:
The present study was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant no. 16K10772) and in part by a grant from the Health Sciences Research Institute, Inc. (Yokohama, Japan) for the Division of Companion Diagnostics, Department of Pathology and Microbiology, Nihon University School of Medicine (Tokyo, Japan).
Funding Information:
The authors declare that they have no competing interests with regard to the subjects discussed in this study. TU received funds for other research projects not related to this study from the Ministry of Education, Culture, Sports, Science and Technology, Japan, the Ministry of Economy, Trade and Industry, Japan and the Human Frontier Science Program, while AY received research funds for another research project from Medtronic Japan Co., Ltd.
Publisher Copyright:
© 2019 Spandidos Publications. All rights reserved.
PY - 2019
Y1 - 2019
N2 - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in cancer cells by binding to its receptors, death receptor 4 (DR4) and DR5, without affecting normal cells, and is therefore considered to be a promising antitumor agent for use in cancer treatment. However, several studies have indicated that most glioma cell lines display resistance to TRAIL-induced apoptosis. To overcome such resistance and to improve the efficacy of TRAIL-based therapies, identification of ideal agents for combinational treatment is important for achieving rational clinical treatment in glioblastoma patients. The main aim of this study was to investigate whether interferon-β (IFN-β) (with its pleiotropic antitumor activities) could sensitize malignant glioma cells to TRAIL-induced apoptosis using glioma cell lines. TRAIL exhibited a dose-dependent antitumor effect in all of the 7 types of malignant glioma cell lines, although the intensity of the effect varied among the cell lines. In addition, combined treatment with TRAIL (low clinical dose: 1 ng/ml) and IFN-β (clinically relevant concentration: 10 IU/ml) in A-172, AM-38, T98G, U-138MG and U-251MG demonstrated a more marked antitumor effect than TRAIL alone. Furthermore, the antitumor effect of the combined treatment with TRAIL and IFN-β may be enhanced via an extrinsic apoptotic system, and upregulation of DR5 was revealed to play an important role in this process in U‑138MG cells. These findings provide an experimental basis to suggest that combined treatment with TRAIL and IFN-β may offer a new therapeutic strategy for malignant gliomas.
AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in cancer cells by binding to its receptors, death receptor 4 (DR4) and DR5, without affecting normal cells, and is therefore considered to be a promising antitumor agent for use in cancer treatment. However, several studies have indicated that most glioma cell lines display resistance to TRAIL-induced apoptosis. To overcome such resistance and to improve the efficacy of TRAIL-based therapies, identification of ideal agents for combinational treatment is important for achieving rational clinical treatment in glioblastoma patients. The main aim of this study was to investigate whether interferon-β (IFN-β) (with its pleiotropic antitumor activities) could sensitize malignant glioma cells to TRAIL-induced apoptosis using glioma cell lines. TRAIL exhibited a dose-dependent antitumor effect in all of the 7 types of malignant glioma cell lines, although the intensity of the effect varied among the cell lines. In addition, combined treatment with TRAIL (low clinical dose: 1 ng/ml) and IFN-β (clinically relevant concentration: 10 IU/ml) in A-172, AM-38, T98G, U-138MG and U-251MG demonstrated a more marked antitumor effect than TRAIL alone. Furthermore, the antitumor effect of the combined treatment with TRAIL and IFN-β may be enhanced via an extrinsic apoptotic system, and upregulation of DR5 was revealed to play an important role in this process in U‑138MG cells. These findings provide an experimental basis to suggest that combined treatment with TRAIL and IFN-β may offer a new therapeutic strategy for malignant gliomas.
KW - Apoptosis
KW - DR5
KW - Glioblastoma
KW - Interferon-β
KW - TRAIL
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U2 - 10.3892/or.2019.7383
DO - 10.3892/or.2019.7383
M3 - Article
C2 - 31638255
AN - SCOPUS:85074502613
VL - 42
SP - 2635
EP - 2643
JO - Oncology Reports
JF - Oncology Reports
SN - 1021-335X
IS - 6
ER -