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Dihydroartemisinin Suppresses Esophageal Squamous Cell Carcinoma by Downregulating COX-2 through the ROS/MAPK/Sp1
Chongbo Liao1, Xingyao Zhu1, Yong Yang1
1Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, P.R. China; School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, P.R. China.
Background:
Esophageal squamous cell carcinoma (ESCC) has a poor prognosis due to its aggressiveness and chemoresistance, necessitating novel therapeutic strategies. Dihydroartemisinin (DHA), an artemisinin derivative, exhibits broad anticancer activity, but its mechanism in ESCC remains incompletely understood.
Methods:
Transcriptomic sequencing identified differentially expressed genes upon DHA treatment. The regulation of COX-2 by DHA was validated via RT-qPCR and Western blot. Gain- and loss-of-function assays assessed COX-2 and Sp1 effects on ESCC proliferation and migration. Dual-luciferase reporter assays confirmed Sp1-driven COX-2 transcription. ROS levels and MAPK pathway protein expression were measured by flow cytometry and Western blot, respectively. A xenograft model evaluated in vivo effects of Sp1 overexpression and DHA.
Results:
DHA downregulated COX-2 in a time- and dose-dependent manner, inhibiting ESCC cell proliferation and migration. Sp1 directly bound the COX-2 promoter and positively regulated its expression, thereby promoting malignant phenotypes. DHA triggered ROS accumulation and downregulated the protein levels of MAPK (ERK/MSK), Sp1, and COX-2. Both NAC (an antioxidant) and Sp1 overexpression reversed these effects. In vivo, DHA significantly suppressed tumor growth via the Sp1/COX-2 axis without detectable toxicity.
Conclusion:
This study establishes that DHA inhibits ESCC proliferation and metastasis through the ROS-MAPK(ERK/MSK)-Sp1-COX-2 axis, highlighting DHA as a promising repurposed agent and identifying Sp1/COX-2 as novel therapeutic targets for ESCC.
