ABSTRACT
Significant changes were observed in the lung imaging of hospitalised COVID-19 patients from 2020 to 2023, with the emergence of more signs of co-infection https://bit.ly/3TaQlJ2.
ABSTRACT
TNFα is a prominent proinflammatory cytokine and a critical mediator for the development of many types of cancer such as breast, colon, prostate, cervical, skin, liver, and chronic lymphocytic leukemia. Binding of TNFα to TNFR1 can lead to divergent signaling pathways promoting predominantly NF-κB activation but also cell death. We report here that the nitric oxide (NO) donor glyceryl trinitrate (GTN) converts TNFα, generated from immune cells or cancer cells stimulated by chemotherapy, into a prodeath mediator in colon and mammary cancer cells. GTN-mediated S-nitrosylation of cIAP1 on cysteines 571 and 574 inhibited its E3 ubiquitin ligase activity, which in turn reduced Lys63-linked ubiquitination of RIP1 and initiated assembly of a death complex. These findings provide insights into how NO can harness advantageous aspects of inflammation in cancer and provide new therapeutic strategies.Significance: Combination of an NO donor with chemotherapeutic drug-induced TNFα represents a potentially valuable anticancer strategy. Cancer Res; 78(8); 1948-57. ©2018 AACR.
Subject(s)
Cell Death/physiology , Cell Survival/physiology , Inhibitor of Apoptosis Proteins/metabolism , Nitroso Compounds/metabolism , Receptors, Tumor Necrosis Factor, Type I/physiology , Tumor Necrosis Factor-alpha/physiology , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , HEK293 Cells , Humans , Irinotecan/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Mice , Nitroglycerin/pharmacology , Oxaliplatin/pharmacology , Signal Transduction , Tumor Necrosis Factor-alpha/biosynthesis , Ubiquitin-Protein Ligases/metabolismABSTRACT
Protein S-nitrosylation is now recognized as a ubiquitous regulatory mechanism. Like any post-translational modifications, S-nitrosylation is critical for the control of numerous cellular processes. It is now clear that S-nitrosylation is playing a double game, enhancing or inhibiting the tumor growth or the induction of cell death. Thanks to research aimed at demonstrating NO cytotoxic effects, new therapeutic strategies based on NO donor drugs have emerged. Although therapeutic NO donors can target a large number of proteins, the cellular mechanism is still not fully understood. This review reflects the current state of knowledge on S-nitrosylated proteins that take part of the oncogenic and apoptotic signaling, putting forward proteins with potential interest in cancer therapy.
Subject(s)
Neoplasms/metabolism , Neoplasms/pathology , Nitric Oxide/physiology , Apoptosis/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Nitric Oxide/pharmacology , Nitrosation , Protein Processing, Post-Translational , Reactive Nitrogen Species/metabolism , Reactive Nitrogen Species/toxicity , Signal Transduction/drug effectsABSTRACT
One of the key features of tumor cells is the acquisition of resistance to apoptosis. Thus, novel therapeutic strategies that circumvent apoptotic resistance and result in tumor elimination are needed. One strategy to induce apoptosis is to activate death receptor signaling pathways. In the tumor microenvironment, stimulation of Fas, Death receptor 4 (DR4) and tumor necrosis factor receptor 1 (TNFR1) can initiate multiple signaling pathways driving either tumor promotion or elimination. Nitric oxide (NO) is an important signaling molecule now understood to play a dual role in cancer biology. More and more attention is directed toward the role displayed by S-nitrosylation, the incorporation of an NO moiety to a cysteine thiol group, in promoting cell death in tumor cells. Protein post-translation modification by S-nitrosylation has decisive roles in regulating signal-transduction pathways. In this review, we summarize several examples of protein modification by S-nitrosylation that regulate signaling pathways engaged by members of the TNF superfamily (Fas ligand (FasL), Tumor-necrosis-factor-related apoptosis inducing ligand (TRAIL) and TNFalpha (TNFα)) and the way it influences cell fate decisions.
