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ID 51445
フルテキストURL
著者
Hasei, Joe Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg
Sasaki, Tsuyoshi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg
Tazawa, Hiroshi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol
Osaki, Shuhei Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg
Yamakawa, Yasuaki Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg
Kunisada, Toshiyuki Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg
Yoshida, Aki Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg
Hashimoto, Yuuri Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol
Onishi, Teppei Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol
Uno, Futoshi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol
Kagawa, Shunsuke Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol
Urata, Yasuo Oncolys BioPharma Inc
Ozaki, Toshifumi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg
Fujiwara, Toshiyoshi Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol
抄録
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.
発行日
2013-03
出版物タイトル
Molecular Cancer Therapeutics
12巻
3号
出版者
Amer Assoc Cancer Research
開始ページ
314
終了ページ
325
ISSN
1535-7163
資料タイプ
学術雑誌論文
オフィシャル URL
http://dx.doi.org/10.1158/1535-7163.MCT-12-0869
関連URL
http://ousar.lib.okayama-u.ac.jp/metadata/51455
言語
English
OAI-PMH Set
岡山大学
著作権者
(C)2012 AACR.
論文のバージョン
author
査読
有り
DOI
Web of Sience KeyUT