Caspase-8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic-induced necroptosis
Caspase-8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCCs), and CASP8 mutations are associated with poor survival. The distribution of these mutations in HNSCCs suggests that they are likely to be inactivating. Inhibition of CASP8 has been reported to sensitize cancer cells to necroptosis, a regulated cell death mechanism. Here, we show that knockdown of CASP8 renders HNSCCs susceptible to necroptosis by a second mitochondria-derived activator of caspase (SMAC) mimetic, birinapant, in combination with pan-caspase inhibitors Z-VAD-FMK or emricasan and radiation. In a syngeneic mouse model of oral cancer, birinapant, particularly when combined with radiation, delayed tumor growth and enhanced survival under CASP8 loss. Exploration of molecular underpinnings of necroptosis sensitivity confirmed that the level of functional receptor-interacting serine/threonine protein kinase 3 (RIP3) determines susceptibility to this mode of death. Although an in vitro screen revealed that low RIP3 levels rendered many HNSCC cell lines resistant to necroptosis, patient tumors maintained RIP3 expression and should therefore remain sensitive. Collectively, these results suggest that targeting the necroptosis pathway with SMAC mimetics, especially in combination with radiation, may be relevant therapeutically in HNSCC with compromised CASP8 status, provided that RIP3 function is maintained.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
JCI insight - 5(2020), 23 vom: 03. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Uzunparmak, Burak [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.05.2021 Date Revised 14.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.139837 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316770426 |
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| 100 | 1 | |a Uzunparmak, Burak |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Caspase-8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic-induced necroptosis |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Completed 24.05.2021 | ||
| 500 | |a Date Revised 14.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Caspase-8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCCs), and CASP8 mutations are associated with poor survival. The distribution of these mutations in HNSCCs suggests that they are likely to be inactivating. Inhibition of CASP8 has been reported to sensitize cancer cells to necroptosis, a regulated cell death mechanism. Here, we show that knockdown of CASP8 renders HNSCCs susceptible to necroptosis by a second mitochondria-derived activator of caspase (SMAC) mimetic, birinapant, in combination with pan-caspase inhibitors Z-VAD-FMK or emricasan and radiation. In a syngeneic mouse model of oral cancer, birinapant, particularly when combined with radiation, delayed tumor growth and enhanced survival under CASP8 loss. Exploration of molecular underpinnings of necroptosis sensitivity confirmed that the level of functional receptor-interacting serine/threonine protein kinase 3 (RIP3) determines susceptibility to this mode of death. Although an in vitro screen revealed that low RIP3 levels rendered many HNSCC cell lines resistant to necroptosis, patient tumors maintained RIP3 expression and should therefore remain sensitive. Collectively, these results suggest that targeting the necroptosis pathway with SMAC mimetics, especially in combination with radiation, may be relevant therapeutically in HNSCC with compromised CASP8 status, provided that RIP3 function is maintained | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Apoptosis pathways | |
| 650 | 4 | |a Cell Biology | |
| 650 | 4 | |a Head and neck cancer | |
| 650 | 4 | |a Oncology | |
| 650 | 4 | |a Radiation therapy | |
| 650 | 7 | |a Apoptosis Regulatory Proteins |2 NLM | |
| 650 | 7 | |a Caspase Inhibitors |2 NLM | |
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| 650 | 7 | |a Mitochondrial Proteins |2 NLM | |
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| 650 | 7 | |a 6O4Z07B57R |2 NLM | |
| 650 | 7 | |a CASP8 protein, human |2 NLM | |
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| 650 | 7 | |a Caspase 8 |2 NLM | |
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| 650 | 7 | |a Caspases |2 NLM | |
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| 700 | 1 | |a Gao, Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Lindemann, Antje |e verfasserin |4 aut | |
| 700 | 1 | |a Erikson, Kelly |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Eric |e verfasserin |4 aut | |
| 700 | 1 | |a Frank, Steven J |e verfasserin |4 aut | |
| 700 | 1 | |a Gleber-Netto, Frederico O |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Skinner, Heath D |e verfasserin |4 aut | |
| 700 | 1 | |a Newton, Jared |e verfasserin |4 aut | |
| 700 | 1 | |a Sikora, Andrew G |e verfasserin |4 aut | |
| 700 | 1 | |a Myers, Jeffrey N |e verfasserin |4 aut | |
| 700 | 1 | |a Pickering, Curtis R |e verfasserin |4 aut | |
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