AI Article Synopsis
- TNFα is a key proinflammatory cytokine involved in various cancers, triggering signals that can lead to cell survival or death through its receptor TNFR1.
- The nitric oxide donor, glyceryl trinitrate (GTN), modifies TNFα's role in colon and mammary cancer cells, making it a pro-death factor following chemotherapy.
- GTN's action reduces the protective activity of cIAP1, promoting a death-inducing complex, suggesting that combining NO donors with chemotherapy may be an effective cancer treatment strategy.
Article 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. Combination of an NO donor with chemotherapeutic drug-induced TNFα represents a potentially valuable anticancer strategy. .
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| http://dx.doi.org/10.1158/0008-5472.CAN-17-2078 | DOI Listing |
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