Under evolutionary pressure from chemotherapy, cancer cells develop resistance characteristics such as a low redox state, which eventually leads to treatment failures. An attractive option for combatting resistance is producing a high concentration of produced free radicals in situ. Here, we report the production and use of dispersible hollow carbon nanospheres (HCSs) as a novel platform for delivering the drug doxorubicine (DOX) and generating additional cellular reactive oxygen species using near-infrared laser irradiation. These irradiated HCSs catalyzed sufficiently persistent free radicals to produce a large number of heat shock factor-1 protein homotrimers, thereby suppressing the activation and function of resistance-related genes. Laser irradiation also promoted the release of DOX from lysosomal DOX@HCSs into the cytoplasm so that it could enter cell nuclei. As a result, DOX@HCSs reduced the resistance of human breast cancer cells (MCF-7/ADR) to DOX through the synergy among photothermal effects, increased generation of free radicals, and chemotherapy with the aid of laser irradiation. HCSs can provide a unique and versatile platform for combatting chemotherapy-resistant cancer cells. These findings provide new clinical strategies and insights for the treatment of resistant cancers.
As one member of 70 kDa heat shock proteins, glucose-regulated protein 78 (GRP78) participates in protein folding, transportation and degradation. This sort of capacity can be enhanced by stresses under which GRP78 is induced rapidly. Unlike its homologues, GRP78 presents multifaceted subcellular position: When ER retention, it serves as the switch of unfolded protein response; When mitochondrial binding, it directly interacts with apoptotic executors; When cell surface residing, it recognizes extracellular ligands, transducing proliferative signals, especially in certain tumors. The close correlation between GRP78 and neoplasm provides us further insight into the event of carcinogenesis and cancer cell chemoresistance, indicating its prognostic predicting significance and validating potential therapeutics for clinical usage, especially because its small molecular inhibitors are emerging quickly these years. What's more, GRP78-related signaling may be helpful for clearer understanding of its biological mechanisms.
The aryl hydrocarbon receptor (AhR) has become increasingly recognized for its role in the differentiation and activity of immune cell subsets; however, its role in regulating the activity of natural killer (NK) cells has not been described. Here, we show that AhR expression is induced in murine NK cells upon cytokine stimulation. We show that in the absence of AhR, NK cells have reduced cytolytic activity and reduced capacity to control RMA-S tumor formation in vivo, despite having normal development and maturation markers. Although AhR was first identified to bind the xenobiotic compound dioxin, AhR is now known to bind a variety of natural exogenous (e.g., dietary) and endogenous ligands. We show that activation of AhR with an endogenous tryptophan derivative, 6-formylindolo[3,2-b]carbazole, potentiates NK cell IFN-γ production and cytolytic activity. Further, administration of 6-formylindolo[3,2-b]carbazole in vivo enhances NK cell control of tumors in an NK cell-and AhR-dependent manner. Finally, similar effects on NK cell potency occur with AhR dietary ligands, potentially explaining the numerous associations that have been observed in the past between diet and NK cell function. Our studies introduce AhR as another regulator of NK cell activity in vivo.FICZ | kynurenine, 3,3′-diindolylmethane (DIM) | indole-3-carbinol (I3C)
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