ID | 51445 |
FullText URL | |
Author |
Hasei, Joe
Sasaki, Tsuyoshi
Osaki, Shuhei
Yamakawa, Yasuaki
Kunisada, Toshiyuki
Kaken ID
researchmap
Yoshida, Aki
Hashimoto, Yuuri
Onishi, Teppei
Uno, Futoshi
Urata, Yasuo
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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.
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Published Date | 2013-03
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Publication Title |
Molecular Cancer Therapeutics
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Volume | volume12
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Issue | issue3
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Publisher | Amer Assoc Cancer Research
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Start Page | 314
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End Page | 325
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ISSN | 1535-7163
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Content Type |
Journal Article
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Official Url | http://dx.doi.org/10.1158/1535-7163.MCT-12-0869
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Related Url | http://ousar.lib.okayama-u.ac.jp/metadata/51455
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language |
English
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Copyright Holders | (C)2012 AACR.
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File Version | author
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Refereed |
True
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DOI | |
Web of Science KeyUT |