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 (Adp53). 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.

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

“…As viruses have developed sophisticated machineries to evade apoptotic cell death and interfere with ER stress and autophagy responses for their survival, 102,103 ICD may have played an essential role in the everlasting war between viruses and their hosts. We and other groups have found that many oncolytic viruses can induce apoptotic cell death and/or necrosis in cancer cells, 9,104,105,106 supporting their immunostimulatory potential to augment antitumor efficacy (Tables 4 and 5). 107,108 CVB3 infection induces multiple DAMPs including ecto-CRT, HMGB1 translocation from nuclei, and ATP release from human lung cancer cells.…”

“…However, there are only two reports showing that virus-induced ecto-CRT was correlated with enhanced intratumoral infiltrations of immune subpopulations, which accounted for the 'in vivo' remarkable antitumor immunity. 9,65 Several studies showed that recombinant oncolytic adenoviruses induced ACD in human malignant glioma cells, 120 brain tumor stem cells, 121 osteosarcoma cells, 105 and lung cancer cells. 122 Newcastle disease virus also triggered autophagy in glioma cells to promote its viral replication.…”

Expression of p53 synergistically augments caspases-mediated apoptosis induced by replication-competent adenoviruses in pancreatic carcinoma cells

“…Previous studies analyzed the role of p53 in replication-competent Ad, which harbored the p53 gene in the same Ad construct and consequently induced p53 expression in coordination with the viral replications. [14][15][16] In contrast to the present study, these reports demonstrated that expression of p53 augmented viral replications or release of viral AsPC-1 cells were uninfected or infected with Ad5-LacZ, Ad5-p53, AdF-Sur, AdF-MK, (3000 vp per cell) or in combination with Ad5-p53 and AdF-Sur or AdF-MK as indicated (3000 vp per cell for respective Ad) and the cell cycle progressions were analyzed with flow cytometry. Average and s.e.…”

“…15,16 These studies did not analyze whether the combinatory effects were additive or synergistic in the cytotoxicity. The experimental systems of the previous studies were not the same as the present study in terms of p53 transduction.…”

Overexpression of Long Non-Coding RNA NNT-AS1 Correlates with Tumor Progression and Poor Prognosis in Osteosarcoma

“…With the advancement of radical surgery and neoadjuvant chemotherapy, the survival rates of osteosarcoma patients have dramatically improved in recent decades [3-6]. However, more than 20% of osteosarcoma patients die from tumor recurrence or metastasis, which remain major obstacles in bone cancer treatment [3, 7].…”