TY - JOUR
T1 - Elimination of MYCN-Amplified Neuroblastoma Cells by Telomerase-Targeted Oncolytic Virus via MYCN Suppression
AU - Tanimoto, Terutaka
AU - Tazawa, Hiroshi
AU - Ieda, Takeshi
AU - Nouso, Hiroshi
AU - Tani, Morimichi
AU - Oyama, Takanori
AU - Urata, Yasuo
AU - Kagawa, Shunsuke
AU - Noda, Takuo
AU - Fujiwara, Toshiyoshi
N1 - Funding Information:
We thank Tomoko Sueishi and Tae Yamanishi for excellent technical support. This study was supported in part by grants from the Japan Agency for Medical Research and Development (to T.F., no. 17ck0106285h001 ) and the Ministry of Education, Culture, Sports, Science, and Technology, Japan (to T.F., nos. 25293283 and 16H05416 ; to H.T., no. 16K10596 ; and to T.T., no. 19K18054 ).
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/9/25
Y1 - 2020/9/25
N2 - Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. High-risk NB is characterized by MYCN amplification and human telomerase reverse transcriptase (hTERT) rearrangement, contributing to hTERT activation and a poor outcome. For targeting hTERT-activated tumors, we developed two oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in which the hTERT promoter drives expression of the viral E1 gene for tumor-specific virus replication. In this study, we demonstrate the therapeutic potential of the hTERT-driven oncolytic adenoviruses OBP-301 and OBP-702 using four human MYCN-amplified NB cell lines (IMR-32, CHP-134, NB-1, LA-N-5) exhibiting high hTERT expression. OBP-301 and OBP-702 exhibited a strong antitumor effect in association with autophagy in NB cells. Virus-mediated activation of E2F1 protein suppressed MYCN expression. OBP-301 and OBP-702 significantly suppressed the growth of subcutaneous CHP-134 tumors. Thus, these hTERT-driven oncolytic adenoviruses are promising antitumor agents for eliminating MYCN-amplified NB cells via E2F1-mediated suppression of MYCN protein.
AB - Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. High-risk NB is characterized by MYCN amplification and human telomerase reverse transcriptase (hTERT) rearrangement, contributing to hTERT activation and a poor outcome. For targeting hTERT-activated tumors, we developed two oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in which the hTERT promoter drives expression of the viral E1 gene for tumor-specific virus replication. In this study, we demonstrate the therapeutic potential of the hTERT-driven oncolytic adenoviruses OBP-301 and OBP-702 using four human MYCN-amplified NB cell lines (IMR-32, CHP-134, NB-1, LA-N-5) exhibiting high hTERT expression. OBP-301 and OBP-702 exhibited a strong antitumor effect in association with autophagy in NB cells. Virus-mediated activation of E2F1 protein suppressed MYCN expression. OBP-301 and OBP-702 significantly suppressed the growth of subcutaneous CHP-134 tumors. Thus, these hTERT-driven oncolytic adenoviruses are promising antitumor agents for eliminating MYCN-amplified NB cells via E2F1-mediated suppression of MYCN protein.
KW - E2F1
KW - MYCN
KW - adenovirus
KW - hTERT
KW - neuroblastoma
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U2 - 10.1016/j.omto.2020.05.015
DO - 10.1016/j.omto.2020.05.015
M3 - Article
AN - SCOPUS:85087090054
SN - 2372-7705
VL - 18
SP - 14
EP - 23
JO - Molecular Therapy - Oncolytics
JF - Molecular Therapy - Oncolytics
ER -
