NF-κB Inhibitor Myrislignan Induces Ferroptosis of Glioblastoma Cells via Regulating Epithelial-Mesenchymal Transformation in a Slug-Dependent Manner

Abstract

Glioblastoma (GBM) is the most common malignant tumor of the adult central nervous system. Aberrant regulation of cell death is an important feature of GBM, and investigating the regulatory mechanisms of cell death in GBM may provide insights into development of new therapeutic strategies. We demonstrated that myrislignan has ferroptosis-promoting activity. Myrislignan is a lignan isolated from Myristica fragrans Houtt and an inhibitor of NF-κB signaling pathway. Ferroptosis is an iron-dependent form of programmed cell death characterized by the accumulation of intracellular lipid peroxidation products. Interestingly, ferroptosis was associated with other biological processes in tumor cells such as autophagy and necroptosis. Recently, the crosstalk between epithelial-mesenchymal transition (EMT) and ferroptosis has also been reported, but the mechanisms underlying the crosstalk have not been identified. Our results indicated that myrislignan suppressed growth of GBM through EMT-mediated ferroptosis in a Slug-dependent manner. Myrislignan inhibited the activation of NF-κB signaling by blocking the phosphorylation of p65 protein and induced ferroptosis through the Slug-SLC7A11 signaling pathway in GBM cells. In addition, myrislignan suppressed the progression of GBM in xenograft mouse model. Hence, our findings contribute to the understanding of EMT-induced ferroptosis and provide targets for the development of targeted therapy against GBM.

Antioxidant Systems as Modulators of Ferroptosis: Focus on Transcription Factors

“…The effect of myrislignan on GBM was confirmed in vivo in the intracranial xenograft model; in particular, Western blot analysis and IHC staining demonstrated that expression of p-p65, Slug, and SLC7A11 declined in myrislignan-treated tumors. Thus, the authors determined that the NF-κB inhibitor myrislignan drives the ferroptosis of glioblastoma cells through Slug–SLC7A11 signaling [ 346 ].…”

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

“… 543 BC Ketamine Acetylation KAT5 Ketamine induces ferroptosis through inhibiting the expression of GPX4 by attenuating KAT5 on the promoter region of GPX4, repressing the enrichment of histone H3 lysine 27 acetylation (H3K27ac) and RNA polymerase II (RNA pol II) 544 GBM ALZ003 Ubiquitination Androgen receptor ALZ003 induces FBXL2-mediated AR ubiquitination and degradation. ALZ003 significantly inhibited the survival of glioblastomathrough inducing ferroptosis 545 Glioma Paeoniflorin Ubiquitination NEDD4L/STAT3 Paeoniflorin might function as an effective drug for glioma by inducing ferroptosis via upregulation of NEDD4L and mediates the ubiquitination of STAT3 repression of Nrf2, GPX4 546 GBM Myrislignan Phosphorylation NF-κB Myrislignan inhibited the activation of NF-κB signaling by blocking the phosphorylation of p65 protein and induced ferroptosis through the Slug-SLC7A11 signaling pathway in GBM cells 547 OC Eriodictyol Phosphorylation Nrf2 Eriodictyol induces ferroptosis through downregulating Nrf2 phosphorylation,thereby decreasing protein levels of SLC7A11 and GPX4 550 Thyroid cancers RSL3 Phosphorylation mTOR RSL3 activate ferroptosis through suppressing mTOR signaling pathway triggered autophagy. GPX4 genetic knockdown mirrored RSL3 effect on mTOR pathway suppression.…”

“… 546 Myrislignan induces ferroptosis through the Slug-SLC7A11 axis by inactivating NF-κB signaling through blockade of p65 phosphorylation in GBM cells. 547 …”

The Recent Research Progress of NF-κB Signaling on the Proliferation, Migration, Invasion, Immune Escape and Drug Resistance of Glioblastoma

“…In addition to inhibiting GBM resistance, some studies have also found that traditional Chinese medicine can directly inhibit NF-κB signaling and promote cell apoptosis. The case in point is that myrislignan inhibits the activation of NF-κB signals by blocking the phosphorylation of p65 proteins, and induces iron death in GBM cells through the Slug-SLC7A11 signal pathway [ 145 ]. Monacolin K (MK), a polyketo secondary metabolic compound of the mold genus monascus, can downregulate JNK/ERK/P65/IκBα expression and promote the phosphorylation of ERK and p65, ultimately resulting in the apoptosis of GBM cells [ 146 ].…”