Curcumin Enhanced Ionizing Radiation-Induced Immunogenic Cell Death in Glioma Cells through Endoplasmic Reticulum Stress Signaling Pathways

Abstract

Objective. Local radiotherapy may cause distant tumor regression via inducing immunogenic cell death (ICD). Here, we investigated the effect of curcumin on ionizing radiation-induced immunogenic cell death in normoxic or hypoxic glioma cells and its mechanism in vitro and vivo. Methods. Hypoxic or normoxic glioma cell apoptosis and the cell surface exposure of calreticulin (CRT) were detected by flow cytometry. Extracellular ATP and HSP70 were measured by chemiluminescence assay and ELISA, respectively. Endoplasmic reticulum (ER) stress protein levels were detected by western blot. Moreover, the induction of bona fide ICD was detected by vaccination assays in mice bearing glioma model. Spleen lymphocytes and tumor-infiltrating lymphocyte subsets were analyzed by flow cytometry and immunohistochemistry. Results. Curcumin incubation before X-ray irradiation significantly increased radiation-induced apoptosis rate in normoxic or hypoxic glioma cells. Curcumin enhanced radiation-induced CRT exposure, release of HSP70 and ATP, and ER stress signaling activity. After treatment with ER stress pathway inhibitors, cell apoptosis and CRT exposure induced by the combination treatment of curcumin and X-ray were reduced. In vaccination experiments, glioma cells irradiated by X-ray produced a strong immunogenic response rejecting tumor formation in 70% mice. In comparison, cells treated by curcumin and X-ray produced a stronger immune response rejecting tumor formation in 90% mice. The combination treatment increased the percentage of tumor-infiltrating CD4+, CD8+ T lymphocytes, and CD11c+ dendritic cells compared to X-ray irradiation alone. Conclusion. Ionizing radiation-induced normoxic or hypoxic glioma immunogenic cell death could be further enhanced by curcumin through activating the ER stress PERK-eIF2α and IRE1α-XBP1 signaling pathways.

A functional medicine and food homology composition discovery based on disease-related target and data mining against cardiac remodeling

“…Among natural product compounds, medicine and food homology (MFH) products have garnered significant attention, served dual roles as essential dietary components, and possessed pharmacological effects that offer the potential to combat diseases and provide health benefits 34 . For instance, S. grosvenorii extract prevents the generation of superoxide anion and inhibits histamine release from mast cells, thereby reducing histamine-induced nose scratching behavior in ICR mice 35 ; Ginsenosides have been found to function as an anti-aging agent by promoting metabolism, protecting the skin and nerves, modulating intestinal flora, and maintaining mitochondrial function 36 ; Nardosinone and aurantio-obtusin are recognized as anti-influenza agents 37 ; Curcumin extracted from turmeric has been identified for its capacity to alleviate radiation-induced cellular damage, providing a protective shield against radiation harm 15, 38 ; Soy isoflavones present in kudzu root exhibit potent free radical scavenging capabilities, mitigating oxidative damage to cells 39, 40 ; Lycium barbarum rich in various antioxidants like polysaccharides and anthocyanins, it demonstrates robust cell protection against oxidative stress, endoplasmic reticulum stress, and autophagy-induced apoptosis 41 ; Ascorbic acid (Vitamin C) serves as a formidable antioxidant, neutralizing free radicals, reducing oxidative damage from UV-Vis irradiation 42 , corneal endothelial damage 43 , and fostering efficient cell repair and regeneration, etc.…”

Clinical application of immunogenic cell death inducers in cancer immunotherapy: turning cold tumors hot

“…Similarly, ER-associated protein degradation inhibitors can interfere with key proteins in the degradation of misfolded proteins, which is conducive to the amplification of mild ERS induced by RT in esophageal squamous cell carcinoma cell lines ( Luo H. et al, 2023 ). In addition, some sensitizers can improve the efficacy of RT by enhancing key events in the RT-induced ICD process, such as inducing intracellular DNA damage ( Zhuang et al, 2023 ), triggering ferroptosis ( Luo et al, 2022 ), and activating ERS PERK-eIF2α and IRE1α-XBP1 signaling pathways ( Xiu et al, 2022 ; Yang et al, 2020 ).…”

Curcuminoids as Anticancer Drugs: Pleiotropic Effects, Potential for Metabolic Reprogramming and Prospects for the Future

“…A second axis, represented by the activation of ER stress produced by curcuminoids, received additional insights through the report that demonstrated an increase of the expression of ATF4 and CHOP [ 47 ]. Two enhanced signaling pathways, PERK-eIF2a and IRE1a-XBP1, were also identified in glioma xenografts in mice following radiotherapy-induced immunogenic cell death [ 69 ]. A third research field was represented by curcumin’s inhibitory effect on proteasome activity, which, at the molecular level, benefited from the demonstration of the involvement of the p300/miR-142-3p/PSMB5 axis [ 27 ].…”