Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated epithelial-to-mesenchymal transition.

Autor: Capobianco E; The Jackson Laboratory, Farmington, CT, United States., McGaughey V; Department of Biology, University of Miami, Coral Gables, FL, United States., Seraphin G; Department of Biology, University of Miami, Coral Gables, FL, United States., Heckel J; Department of Biology, University of Miami, Coral Gables, FL, United States., Rieger S; Department of Biology, University of Miami, Coral Gables, FL, United States.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States., Lisse TS; Department of Biology, University of Miami, Coral Gables, FL, United States.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States.; iCURA DX, Malvern, PA, United States.
Jazyk: angličtina
Zdroj: Frontiers in oncology [Front Oncol] 2023 May 09; Vol. 13, pp. 1188641. Date of Electronic Publication: 2023 May 09 (Print Publication: 2023).
DOI: 10.3389/fonc.2023.1188641
Abstrakt: Osteosarcomas are immune-resistant and metastatic as a result of elevated nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT). Although vitamin D has anti-cancer effects, its effectiveness and mechanism of action against osteosarcomas are poorly understood. In this study, we assessed the impact of vitamin D and its receptor (VDR) on NMD-ROS-EMT signaling in in vitro and in vivo osteosarcoma animal models. Initiation of VDR signaling facilitated the enrichment of EMT pathway genes, after which 1,25(OH) 2 D, the active vitamin D derivative, inhibited the EMT pathway in osteosarcoma subtypes. The ligand-bound VDR directly downregulated the EMT inducer SNAI2 , differentiating highly metastatic from low metastatic subtypes and 1,25(OH) 2 D sensitivity. Moreover, epigenome-wide motif and putative target gene analysis revealed the VDR's integration with NMD tumorigenic and immunogenic pathways. In an autoregulatory manner, 1,25(OH) 2 D inhibited NMD machinery genes and upregulated NMD target genes implicated in anti-oncogenic activity, immunorecognition, and cell-to-cell adhesion. Dicer substrate siRNA knockdown of SNAI2 revealed superoxide dismutase 2 (SOD2)-mediated antioxidative responses and 1,25(OH) 2 D sensitization via non-canonical SOD2 nuclear-to-mitochondrial translocalization leading to overall ROS suppression. In a mouse xenograft metastasis model, the therapeutically relevant vitamin D derivative calcipotriol inhibited osteosarcoma metastasis and tumor growth shown for the first time. Our results uncover novel osteosarcoma-inhibiting mechanisms for vitamin D and calcipotriol that may be translated to human patients.
Competing Interests: TL was employed by iCURA LLC.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Capobianco, McGaughey, Seraphin, Heckel, Rieger and Lisse.)
Databáze: MEDLINE
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