Canagliflozin ameliorates progestin resistance by suppressing RARb/CRABP2 signaling in TRb knockout endometrial cancer cells

THRB-knockout RL95-2 (THRB(-/-)/RL95-2) cells were constructed toinvestigate progestin resistance mechanisms. Cell proliferation and apoptosis wereassessed in RL95-2 and THRB(-/-)/RL95-2 cells treated with canagliflozin (CANA),medroxyprogesterone acetate (MPA), or their combination using CCK-8, EdU, andflow cytometry assays. In vivo, nude mouse xenograft models were used to evaluateCANA and MPA efficacy. Transcriptomic and proteomic analyses identified pathwaysassociated with progestin resistance. Molecular dynamics simulations, western blotting,and immunohistochemistry identified CANA targets. Electrophoretic mobility shiftassays and dual luciferase reporter assays evaluated the regulatory effects of TRb,RARb, and CRABP2.