Immunomodulator polyinosinic-polycytidylic acid enhances the inhibitory effect of 13-cis-retinoic acid on neuroblastoma through a TLR3-related immunogenic-apoptotic response
Journal
Laboratory Investigation
Journal Volume
100
Journal Issue
4
Pages
606-618
Date Issued
2020
Author(s)
Abstract
High-risk neuroblastoma is associated with low long-term survival rates due to recurrence or metastasis. Retinoids, including 13-cis-retinoic acid (13cRA), are commonly used for the treatment of high-risk neuroblastoma after myeloablative therapy; however, there are significant side effects and resistance rates. In this study, we demonstrated that 13cRA has a better antiproliferative effect in MYCN-amplified neuroblastoma cells than in MYCN-nonamplified neuroblastoma cells. In MYCN-amplified SK-N-DZ cells, 13cRA induced significant upregulation of toll-like receptor 3 (TLR3) and mitochondrial antiviral-signaling protein (MAVS) expression in a time-dependent manner. Furthermore, poly (I:C), a synthetic agonist of TLR3, effectively synergized with 13cRA to enhance antiproliferative effects through upregulation of the innate immune signaling and the mitochondrial stress response, leading to augmentation of the apoptotic response in 13cRA-responsive cancer cells. In addition, the 13cRA/poly (I:C) combination induced neural differentiation through activation of retinoic acid receptors beta (RAR-β), restoring expression of α-thalassemia/mental retardation syndrome X-linked (ATRX) protein, and inhibiting vessel formation, leading to retarded tumor growth in a mouse xenograft model. These results suggest that the combination of poly (I:C) and RA may provide synergistic therapeutic benefits for treatment of patients with high-risk neuroblastoma. ? 2019, The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.
SDGs
Other Subjects
caspase 3; caspase 9; cytochrome c; isotretinoin; polyinosinic polycytidylic acid; retinoic acid receptor beta; toll like receptor 3; antineoplastic agent; immunologic factor; isotretinoin; polyinosinic polycytidylic acid; toll like receptor 3; alpha thalassemia-mental retardation syndrome X-linked; animal experiment; animal model; antiproliferative activity; apoptosis; Article; cell differentiation; cell proliferation; controlled study; endothelium cell; high risk patient; human; human cell; immune response; immunohistochemistry; in vitro study; in vivo study; limit of quantitation; male; mouse; nerve cell differentiation; neuroblastoma; nonhuman; priority journal; protein cleavage; protein expression; SK-N-AS cell line; SK-N-BE(2)-M17 cell line; SK-N-DZ cell line; SK-N-FI cell line; tumor growth; tumor xenograft; upregulation; Western blotting; animal; apoptosis; cell line; drug effect; drug potentiation; drug screening; metabolism; neuroblastoma; SCID mouse; signal transduction; Animals; Antineoplastic Agents; Apoptosis; Cell Line; Cell Proliferation; Drug Synergism; Immunologic Factors; Isotretinoin; Male; Mice; Mice, SCID; Neuroblastoma; Poly I-C; Signal Transduction; Toll-Like Receptor 3; Xenograft Model Antitumor Assays
Publisher
Springer Nature
Type
journal article