title: Dual programmed cell death pathways induced by p53 transactivation overcome resistance to oncolytic adenovirus in human osteosarcoma cells.
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.
authors: Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors: Joe
authors: J
authors: Hasei
authors: Tsuyoshi
authors: T
authors: Sasaki
authors: Hiroshi
authors: H
authors: Tazawa
authors: Shuhei
authors: S
authors: Osaki
authors: Yasuaki
authors: Y
authors: Yamakawa
authors: Toshiyuki
authors: T
authors: Kunisada
authors: Aki
authors: A
authors: Yoshida
authors: Yuuri
authors: Y
authors: Hashimoto
authors: Teppei
authors: T
authors: Onishi
authors: Futoshi
authors: F
authors: Uno
authors: Shunsuke
authors: S
authors: Kagawa
authors: Yasuo
authors: Y
authors: Urata
authors: Toshifumi
authors: T
authors: Ozaki
authors: Toshiyoshi
authors: T
authors: Fujiwara
mesh_terms: D000256:Adenoviridae; D017209:Apoptosis / Q000235:genetics; D001859:Bone Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D002453:Cell Cycle / Q000235:genetics; D006801:Humans; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D012516:Osteosarcoma / Q000473:pathology / Q000628:therapy* / Q000821:virology; D015533:Transcriptional Activation / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53