TY  - EJOU
AU  - Zhang, Yizhen 
AU  - Li, Juan 
AU  - Liu, Huanqing 
AU  - Xia, Hong 
AU  - Su, Jian 
AU  - Liu, Fang 
AU  - Su, Bo 
AU  - Su, Qi 

TI  - DADS Regulates EMT and Chemotherapy Resistance by Inhibiting ROR<b>α</b>/<b>β</b>-Catenin Signaling through PKC<b>α</b>-Dependent Phosphorylation in Gastric Cancer
T2  - Oncology Research

PY  - 2025
VL  - 33
IS  - 12
SN  - 1555-3906

AB  -  <b>Objectives:</b> 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. <b>Methods:</b> 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 <i>t</i>-test/ANOVA (<i>p</i> < 0.05). <b>Results:</b> 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. <b>Conclusion:</b> 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.
KW  - Diallyl disulfide; retinoid-related orphan receptor alpha (RORα)/β-catenin signaling; gastric cancer cells; epithelial-mesenchymal transition; drug resistance

DO  - 10.32604/or.2025.068689