Curcumin induces ferroptosis and apoptosis in osteosarcoma cells by regulating Nrf2/GPX4 signaling pathway

Abstract

Curcumin, an antitumor agent, has been shown to inhibit cell growth and metastasis in osteosarcoma. However, there is no evidence of curcumin and its regulation of cell ferroptosis and nuclear factor E2–related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathways in osteosarcoma. This study aimed to investigate the effects of curcumin on osteosarcoma both in vitro and in vivo. To explore the effects and mechanisms of curcumin on osteosarcoma, cells (MNNG/HOS and MG-63) and xenograft mice models were established. Cell viability, cell apoptosis rate, cycle distribution, cell migration, cell invasion, reactive oxygen species, malonaldehyde and glutathione abilities, and protein levels were detected by cell counting kit-8, flow cytometry, wound healing, transwell assay, respectively. Nrf2 and GPX4 expressions were detected using an immunofluorescence assay. Nrf2/GPX4-related protein levels were detected using western blotting. The results showed that curcumin effectively decreased cell viability and increased apoptosis rate. Meanwhile, curcumin inhibited tumor volume in the xenograft model, and Nrf2/GPX4-related protein levels were also altered. Interestingly, the effects of curcumin were reversed by liproxstatin-1 (an effective inhibitor of ferroptosis) and bardoxolone-methyl (an effective activator of Nrf2). Our results indicate that curcumin has therapeutic effects on osteosarcoma cells and a xenograft model by regulating the expression of the Nrf2/GPX4 signaling pathway.

Ferroptosis defense mechanisms: The future and hope for treating osteosarcoma

“…This effect can be reversed by the ferroptosis inhibitor Liproxstatin-1 (Lip-1) and the Nrf2 activator Bardoxolone methyl. 93 Additionally, the curcumin analog EF24 induces ferroptosis in OS cells by upregulating the expression of the ferroptosis-related gene HMOX1, without inducing other forms of cell death such as apoptosis, necroptosis, or autophagy. 92 The synthesis of AA is closely linked to the specific structural domain of ACSL3, and the splicing of ACSL3 pre-mRNA mediated by BRD4-SRPK2-SRSF2 enhances erastin-induced ferroptosis in OS cells.…”

Amicis Omnia Sunt Communia: NF-κB Inhibition as an Alternative to Overcome Osteosarcoma Heterogeneity

“…Curcumin—This polyphenol derived from the turmeric rhizome of Curcuma longa L. is extensively described as an antitumor agent capable of constraining NF-κB pathway activation by interfering with IKK and blocking IκBα and p65 phosphorylation [ 305 ]. The literature reports numerous curcumin antiproliferative and antimigratory effects on OS with modulation of p21, Bax, Bcl-xl, Bcl2, caspase-3, PARP cleavage, cyclin D1, MMP-2, and MMP-9 expression [ 306 , 307 , 308 , 309 , 310 , 311 ].…”