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 expl...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(RORα)to weaken the protein kinase C alpha(PKCα)/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,RORαagonist SR1078/antagonist T0901317,and PKCαagonist 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 nuclearβ-catenin/TGF-β1/Rac1/Vimentin,and weakened EMT(reversed by T0901317).DADS/TPA upregulated RORα/p-RORα/PKCα/p-PKCα,promoted PKCα-RORαbinding,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 RORαagonist for GC therapy.展开更多
基金supported by The National Natural Scientific Foundation of China(No.81973532,No.81374013)The Natural Science Foundation of Hunan Province of China(No.2020JJ4522,No.2020JJ4529)+4 种基金The Patency Foundation of Innovation Platform of Hunan Provincial University of China(No.17K081)The Scientific Research Foundation ofHealth and Family Planning Committee of Hunan Province of China(No.A2015-2,No.B2015-182)The Scientific Research Foundation of Hunan Province Education Department of China(No.19C1610)Science and Technology Project of Jiangxi Provincial Administration of Traditional Chinese Medicine(No.2021B715)The Scientific Research Foundation of University of South China(No.220XNK002).
文摘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(RORα)to weaken the protein kinase C alpha(PKCα)/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,RORαagonist SR1078/antagonist T0901317,and PKCαagonist 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 nuclearβ-catenin/TGF-β1/Rac1/Vimentin,and weakened EMT(reversed by T0901317).DADS/TPA upregulated RORα/p-RORα/PKCα/p-PKCα,promoted PKCα-RORαbinding,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 RORαagonist for GC therapy.
