Cimigenoside enhances Taxol chemosensitivity in triple-negative breast cancer via the γ-secretase/RBPJ-PXR axis.

[BACKGROUND AND PURPOSE] Previous studies have found that activation of the γ-secretase/NICD-PXR/Notch pathway can induce Taxol resistance in triple-negative breast cancer (TNBC) to limit its therapeutic effect. Accordingly, inhibition of the γ-secretase/Notch pathway maybe an effective strategy to enhance Taxol chemosensitivity in TNBC. We have already found that cimigenoside (CG), the active ingredient of Cimicifuga dahurica (Turcz.) Maxim, can inhibit γ-secretase activity.

[EXPERIMENTAL APPROACH] The dynamic interaction between the natural γ-secretase inhibitor CG and γ-secretase catalytic core presenilin-1 (PSEN-1) was revealed by molecular dynamics simulations and in vitro enzyme activity experiments. The biological characterisation and in vivo role of CG in increasing Taxol sensitivity of TNBC were investigated. The regulatory effect of CG on the γ-secretase/RBPJ-PXR axis was studied through dual luciferase reporter gene assays, nuclear cytoplasmic separation experiments, and western blot assays.

[KEY RESULTS] CG stably binds to the PSEN-1 protein cavity to inhibit γ-secretase activity. In vitro studies showed that CG significantly enhanced the inhibition of cell proliferation, migration and invasion, as well as the promotion of apoptosis of MDA-MB-231/Taxol cells by Taxol. CG enhanced the inhibitory effect of Taxol on subcutaneous tumours and lung metastatic TNBC in vivo. Mechanistically, CG inhibited the transcriptional activity of RBPJ by targeting γ-secretase, interfered with the interaction between RBPJ and pregnane X receptor (PXR), down-regulated the expression of PXR-regulated metabolic enzymes and transport proteins, and enhanced the sensitivity of TNBC to Taxol.

[CONCLUSIONS AND IMPLICATIONS] We show that CG enhances the chemical sensitivity of TNBC by regulating the γ-secretase/RBPJ-PXR axis.