海洋来源curdepsidone A通过调控ER应激和PERK/ATF4/CHOP通路抑制HeLa细胞增殖

Abstract

Cervical cancer represents a major malignancy that poses a serious threat to women's health. Curdepsidone A (CDA), a depsidone-type compound isolated from the secondary metabolites of the marine-derived endophytic fungus Curvularia sp. IFB-Z10, has been shown to inhibit the proliferation of cervical cancer HeLa cells and to induce apoptosis. This study aimed to elucidate the key signaling pathways underlying CDA-induced apoptosis in HeLa cells. Omics analysis revealed that CDA affected protein processing in endoplasmic reticulum (ER) in HeLa cells. Western blotting and siRNA-mediated gene silencing revealed that CDA promoted apoptosis by activating the PERK/ATF4/CHOP signaling pathway. Additionally, CDA bound to the kinase domain of IRE1α, inhibited its kinase activity but paradoxically enhanced its RNase activity via allosteric modulation. Furthermore, activation of the ATF6 pathway did not directly contribute to apoptosis. Finally, a xenograft nude mouse model was used to evaluate the in vivo effects and mechanisms of CDA. The results demonstrated that CDA effectively inhibited the proliferation of HeLa cells in vivo and induced apoptosis by upregulating ATF4 levels, consistent with the in vitro findings. In conclusion, our findings indicate that CDA induces sustained ER stress, thereby activating the PERK/ATF4/CHOP pathway to trigger apoptosis in HeLa cells. Together, these findings define CDA as a novel marine-derived depsidone scaffold that induces apoptosis via sustained ER stress signaling and provides a basis for future structure optimization.