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.
Highlights
IntroductionTNFa is one of the most important proinflammatory cytokines that contribute to tumor development, making TNFa-mediated signaling pathways important targets for cancer therapy [1, 2]
TNFa is one of the most important proinflammatory cytokines that contribute to tumor development, making TNFa-mediated signaling pathways important targets for cancer therapy [1, 2].Upon TNFa stimulation, tumor necrosis factor receptor 1 (TNFR1) can mediate signals for either cell survival (NF-kB pathway) or cell death [2]
Our findings show that nitric oxide (NO) compromises cIAP1 ubiquitin E3 ligase activity and that the S-nitrosylation at position Cys571 appears important in this process
Summary
TNFa is one of the most important proinflammatory cytokines that contribute to tumor development, making TNFa-mediated signaling pathways important targets for cancer therapy [1, 2]. Upon TNFa stimulation, tumor necrosis factor receptor 1 (TNFR1) can mediate signals for either cell survival (NF-kB pathway) or cell death [2]. Within complex I, cIAP-mediated Lysine 63 (Lys63)–linked ubiquitination of RIP1 is required for TNFa-induced activation of NF-kB [3]. Cell fate decision predominantly relies on the Lys63-linked ubiquitination status of RIP1 [2, 4]. TNFa/TNFR1 mediates the assembly of a complex II, recruits nonubiquitinated RIP1 (dissociated from complex I), and promotes cell death [2]
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