Arsenic Trioxide Induces Retinoic Acid-Related Orphan Receptor Beta and Blocks the WNT Pathway to Inhibit Stemness in Glioblastoma

Arsenic Trioxide Induces Retinoic Acid-Related Orphan Receptor Beta and Blocks the WNT Pathway to Inhibit Stemness in Glioblastoma

Dacheng Ding,¹ Kaiming Gao,¹ Xuebin Zhang² and Hu Wang^1,3

¹Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, P.R. China
²Department of Pathology, Tianjin Huanhu Hospital, Tianjin, P.R. China
³Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, Tianjin, China

Glioblastoma (GBM) is a malignant primary brain tumor and an essential contributor to morbidity and mortality globally. Arsenic trioxide (ATO) exerts specific roles in preventing tumor growth. This study investigated the role of ATO in GBM cell behaviors and stemness. The effects of ATO on the malignant behavior of GBM cells, tumor stemness, and epithelial-mesenchymal transition (EMT) factors in mouse tumor tissues were explored. Targets of ATO in GBM were predicted using multiple databases. Subsequently, the expression of retinoic acid-related orphan receptor beta (RORB), WNT-1, β-Catenin, and c-Myc expression were examined in GBM cells before and after ATO treatment. ATO inhibited the malignant behavior of GBM cells in vitro and slowed down the GBM growth in vivo by inhibiting the stemness. The inhibitory effect of ATO on GBM was achieved by promoting RORB levels and strengthening the antagonism to β-Catenin to inhibit Wnt signaling, thus inhibiting tumor growth. Collectively, ATO induced RORB levels in GBM cells and strengthened the antagonistic effect on β-Catenin, thus inhibiting WNT signaling and tumor growth.

Key words —— arsenic trioxide; β-Catenin; cell stemness; glioblastoma; WNT signaling pathway

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Tohoku J. Exp. Med., 2024 July, 263(3), 199-210.

Correspondence: Hu Wang, Department of Neurosurgery, Tianjin Huanhu Hospital, No.6, Jizhao Road, Jinnan District, Tianjin 300350, P.R. China. Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, Tianjin, China.

e-mail: wangh3212@163.com