Open Access

ARTICLE

DADS Regulates EMT and Chemotherapy Resistance by Inhibiting RORα/β-Catenin Signaling through PKCα-Dependent Phosphorylation in Gastric Cancer

Yizhen Zhang^1,2,#, Juan Li^1,3,#, Huanqing Liu^1,4,#, Hong Xia¹, Jian Su^1,5, Fang Liu¹, Bo Su^6,*, Qi Su^1,*

1 Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, 421001, China
2 Department of Pathology, The Affiliated Hospital, Jinggangshan University, Ji’an, 343000, China
3 Department of Geriatric Medicine, Loudi Central Hospital, Loudi, 417000, China
4 Department of Oncology, Changsha County People’s Hospital, Changsha, 410100, China
5 Hunan Clinical Research Center for Gastric Cancer Prevention and Treatment, Second Affiliated Hospital, University of South China, Hengyang, 421001, China
6 Key Laboratory for Pharmacoproteomics of Hunan Provincial University, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, 421001, China

* Corresponding Authors: Bo Su. Email: ; Qi Su. Email:
# These authors contributed equally to this work

(This article belongs to the Special Issue: Signaling Pathway Crosstalk in Malignant Tumors: Molecular Targets and Combinatorial Therapeutics)

Oncology Research 2025, 33(12), 3869-3886. https://doi.org/10.32604/or.2025.068689

Received 04 June 2025; Accepted 24 September 2025; Issue published 27 November 2025

Abstract

Objectives: Gastric cancer (GC) is often associated with high invasiveness, epithelial-mesenchymal transition (EMT), and resistance to 5-fluorouracil (5-FU), highlighting the need for novel therapeutic targets. This study explored whether diallyl disulfide (DADS) upregulates retinoic acid-related orphan receptor alpha (ROR) to weaken the protein kinase C alpha (PKC)/RORα-mediated RORα/β-catenin pathway, thereby inhibiting GC cell invasion, epithelial-mesenchymal transition (EMT), and enhancing 5-FU sensitivity. Methods: Human GC cell lines MGC-803 and SGC7901 were treated with DADS, RORα agonist SR1078/antagonist T0901317, and PKCα agonist TPA/antagonist GO6976. Cell proliferation (MTT), migration (scratch assay), invasion (Transwell), protein expression (Western blot), protein interactions (coimmunoprecipitation), and localization (immunofluorescence) were detected. Apoptosis and 5-FU sensitivity-related proteins were examined. Experiments were triplicated; statistics used t-test/ANOVA (p < 0.05). Results: DADS/SR1078 inhibited GC cell proliferation/migration/invasion, upregulated RORα/E-cadherin, downregulated nuclear β-catenin/TGF-β1/Rac1/Vimentin, and weakened EMT (reversed by T0901317). DADS/TPA upregulated RORα/p-RORα/PKCα/p-PKCα, promoted PKCα-RORα binding, and downregulated RORα/β-catenin target genes (counteracted by GO6976). DADS upregulated caspase-3 and downregulated Bcl-2/P-gp/XIAP via RORα, promoting apoptosis and 5-FU sensitivity. Conclusion: DADS inhibits GC progression and enhances 5-FU sensitivity by PKCα/RORα-mediated downregulation of RORα/β-catenin signaling, paralleling SR1078/TPA effects. It may act as a novel RORα agonist for GC therapy.

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