Dioscin Suppresses Ovarian and Gastric Tumor Progression by Inhibiting
ALDH1A3
‐Mediated Retinoic Acid Metabolism and Cancer Stemness
ABSTRACT
Background
ALDH1A3 is a key factor associated with tumor stemness and chemotherapy resistance, making it a promising therapeutic target. Screening various compounds with potential inhibition of cancer stem cells led to the discovery of a naturally occurring Dioscin as a novel ALDH1A3 inhibitor. However, the precise mechanism underlying its action remains unexplored.
Experimental Procedure
Immunohistochemical analysis of 90 ovarian serous tumor samples revealed the clinical significance of ALDH1A3 in tumor progression. TCGA data was used to identify genes highly correlated with ALDH1A3 in ovarian cancer. Using CRISPR/Cas9‐generated
ALDH1A3
knockout (KO) cell lines, we investigated its oncogenic influence in ovarian and gastric cancers. The anti‐tumor effects of Dioscin were assessed through MTT, scratch, and 3D spheroid formation assays. In vivo efficacy of Dioscin was assessed using a xenograft mouse model. Mechanistic investigations of Dioscin with ALDH1A3 were predicted by molecular docking and assessed through ALDH1A3 enzymatic activity and retinoic acid (RA) metabolism analyses.
Results
ALDH1A3 expression correlates with early‐stage ovarian cancer progression. Genetic ablation of
ALDH1A3
significantly suppressed cell proliferation, migration, and stemness properties. ALDH1A3 is significantly associated with ECM‐related genes in ovarian cancer. Dioscin exhibited an ALDH1A3‐dependent anti‐tumor effect by inhibiting ALDH1A3 enzymatic activity, disrupting RA metabolism, and downregulating the expression of stemness‐ and migration‐associated proteins (CD44 and MMP2). Furthermore, Dioscin effectively delays tumor growth without obvious signs of toxicity.
Conclusion
Our study provides the first evidence that Dioscin inhibits ALDH1A3‐mediated RA metabolism and cancer stemness. Our data will further support its potential as a therapeutic agent for cancer treatment.
