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ID 51445
FullText URL
Author
Hasei, Joe
Sasaki, Tsuyoshi
Tazawa, Hiroshi ORCID Kakenhi publons
Osaki, Shuhei
Yamakawa, Yasuaki
Yoshida, Aki
Hashimoto, Yuuri
Onishi, Teppei
Uno, Futoshi
Kagawa, Shunsuke ORCID Kakenhi
Urata, Yasuo
Fujiwara, Toshiyoshi ORCID Kakenhi
Abstract
Tumor suppressor p53 is a multifunctional transcription factor that regulates diverse cell fates, including apoptosis and autophagy in tumor biology. p53 overexpression enhances the antitumor activity of oncolytic adenoviruses; however, the molecular mechanism of this occurrence remains unclear. We previously developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301, that kills human osteosarcoma cells, but some human osteosarcoma cells were OBP-301-resistant. In this study, we investigated the antitumor activity of a p53-expressing oncolytic adenovirus, OBP-702, and the molecular mechanism of the p53-mediated cell death pathway in OBP-301-resistant human osteosarcoma cells. The cytopathic activity of OBP-702 was examined in OBP-301-sensitive (U2OS and HOS) and OBP-301-resistant (SaOS-2 and MNNG/HOS) human osteosarcoma cells. The molecular mechanism in the OBP-702-mediated induction of two cell death pathways, apoptosis and autophagy, was investigated in OBP-301-resistant osteosarcoma cells. The antitumor effect of OBP-702 was further assessed using an orthotopic OBP-301-resistant MNNG/HOS osteosarcoma xenograft tumor model. OBP-702 suppressed the viability of OBP-301-sensitive and -resistant osteosarcoma cells more efficiently than OBP-301 or a replication-deficient p53-expressing adenovirus (Ad-p53). OBP-702 induced more profound apoptosis and autophagy when compared with OBP-301 or Ad-p53. E1A-mediated miR-93/106b upregulation induced p21 suppression, leading to p53-mediated apoptosis and autophagy in OBP-702-infected cells. p53 overexpression enhanced adenovirus-mediated autophagy through activation of damage-regulated autophagy modulator (DRAM). Moreover, OBP-702 suppressed tumor growth in an orthotopic OBP-301-resistant MNNG/HOS xenograft tumor model. These results suggest that OBP-702-mediated p53 transactivation is a promising antitumor strategy to induce dual apoptotic and autophagic cell death pathways via regulation of miRNA and DRAM in human osteosarcoma cells. Mol Cancer Ther; 12(3); 314-25.
Published Date
2013-03
Publication Title
Molecular Cancer Therapeutics
Volume
volume12
Issue
issue3
Publisher
Amer Assoc Cancer Research
Start Page
314
End Page
325
ISSN
1535-7163
Content Type
Journal Article
Official Url
http://dx.doi.org/10.1158/1535-7163.MCT-12-0869
Related Url
http://ousar.lib.okayama-u.ac.jp/metadata/51455
language
英語
Copyright Holders
(C)2012 AACR.
File Version
author
Refereed
True
DOI
Web of Sience KeyUT