Terrestrosin D promotes autophagy and apoptosis of breast cancer cells through PSMD1-dependent activation of P53 pathway

Background and purpose

Breast cancer, particularly triple-negative breast cancer (TNBC), poses a significant threat to women's health. In tumor cells, autophagy and apoptosis are double-edged swords, playing complex roles in cancer progression and treatment. This study aimed to investigate whether Terrestrosin D (TED) exerts antitumor effects on TNBC by modulating autophagy and apoptosis, and to elucidate the underlying molecular mechanisms.

Methods

The antiproliferative and pro-apoptotic effects of TED on TNBC cells were assessed using CCK-8, EdU assay, Live/Dead staining, and flow cytometry. Autophagy was monitored through immunofluorescence and confocal microscopy. RNA sequencing was performed to identify the pathways and molecular targets involved. The anti-TNBC effects of TED were further evaluated in vivo using tumor xenograft models. Western blotting was conducted to validate the relationship between PSMD1, P53, and TED-induced antitumor activity.

Results

TED exhibited significant antitumor effects both in vitro and in vivo. Cellular phenotypic analyses revealed that TED promoted autophagy and apoptosis. Transcriptomic analyses indicated that TED stabilizes P53 expression and activates the P53 signaling pathway by inhibiting the function of PSMD1.

Conclusion

TED exhibits potent antitumor effects on TNBC by promoting autophagy and apoptosis. It achieves this through PSMD1 inhibition, stabilizing P53 expression, and activating the P53 pathway. Notably, this study is the first to demonstrate that TED directly targets PSMD1, a key proteasomal regulator, thereby unveiling a novel mechanism for P53 stabilization in TNBC. These findings provide new insights into the therapeutic modulation of the PSMD1 - P53 axis by natural compounds and support the development of TED as a multi-functional agent for aggressive breast cancers.