Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells

被引:58
作者
Hasei, Joe [1 ]
Sasaki, Tsuyoshi [1 ]
Tazawa, Hiroshi [2 ,4 ]
Osaki, Shuhei [1 ]
Yamakawa, Yasuaki [1 ]
Kunisada, Toshiyuki [1 ,3 ]
Yoshida, Aki [1 ]
Hashimoto, Yuuri [2 ]
Onishi, Teppei [2 ]
Uno, Futoshi [2 ]
Kagawa, Shunsuke [2 ]
Urata, Yasuo [5 ]
Ozaki, Toshifumi [1 ]
Fujiwara, Toshiyoshi [2 ]
机构
[1] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg, Okayama 7008558, Japan
[2] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Surg Gastroenterol, Okayama 7008558, Japan
[3] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med Mat Musculoskeletal Reconstruct, Okayama 7008558, Japan
[4] Okayama Univ Hosp, Ctr Innovat Clin Med, Okayama, Japan
[5] Oncolys BioPharma Inc, Tokyo, Japan
关键词
GENE-THERAPY; TELOMERASE ACTIVITY; PROGNOSTIC-FACTORS; DOWN-REGULATION; EXPRESSING P53; CANCER-CELLS; LUNG-CANCER; SOFT-TISSUE; APOPTOSIS; GROWTH;
D O I
10.1158/1535-7163.MCT-12-0869
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (C)2012 AACR.
引用
收藏
页码:314 / 325
页数:12
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