VALD-3 suppresses triple negative breast cancer progression via Caspase 3/GSDME-dependent pyroptosis

Abstract

yroptosis, an inflammatory form of Programmed cell death (PCD) and so far, the function of Schiff base compounds in pyroptosis cell death has not been reported. Here, we show that VALD3, a Ligand derivative of Schiff base, treated Triple negative breast cancer (TNBC) cells exhibited specific pyroptotic characteristics, including cell swelling, balloon-like bubbling and inflammatory cytokine release through pore formation in the plasma membrane, eventually suppressing the tumor growth of TNBC. In addition, Western blot analysis revealed that the cleavage of Gasdermin E (GSDME),was related to the activation of caspase-3 in TNBC cells treated by VALD3. Consistent with this, treatment with zDEVD-FMK,a caspase-3 specific inhibitor,reduces VALD3-induced GSDME–N-terminal fragment cleavage and pyroptosis. Mechanistically, VALD3 elevated the level of reactive oxygen species(ROS)and c-Jun NH2-terminal kinase (JNK)phosphorylation.NAC,a ROS scavenger,reversed the pyroptosis and JNK phosphorylation in MDA-MB-468 and MDA-MB-231 treated by VALD3. Activated JNK recruited Bax to mitochondria to form a heterodimer with Bcl-2, which stimulated the release of cytochrome c into the cytoplasm, followed by caspase-3 activation and GSDME-depended pyroptosis in TNBC cells. Therefore, in TNBC cells,VALD-3 treatment induces the ROS/JNK/Bax-mitochondrial apoptosis pathway. Thereby activating Caspase-3 and inducing cleavage of GSDME to execute pyroptosis. These findings bring an unexpected concept that GSDME-dependent pyroptosis is an unrecognized mechanism by which VALD3 eradicates neoplastic cells, and provide new insights into the clinical application of anticancer therapeutics.

Mechanism of ferroptosis in breast cancer and research progress of natural compounds regulating ferroptosis

“…[233][234][235] Yan et al found that cryptotanshinone inhibits tumour growth by promoting ferroptosis in granulocytic myeloid-derived suppressor cells and TNBC cells through proteomics, single-cell transcriptome sequencing, ferroptosis phenotype detection, DARTS, microthermophoresis and molecular docking. 236…”