Loss of Caspase-8 function in combination with SMAC mimetic treatment sensitizes Head and Neck Squamous Carcinoma to radiation through induction of necroptosis
| Autor: | Burak Uzunparmak, Meng Gao, Antje Lindemann, Kelly Erikson, Li Wang, Eric Lin, Steven J. Frank, Frederico O. Gleber-Netto, Mei Zhao, Heath D. Skinner, Jared Newton, Andrew G. Sikora, Jeffrey N. Myers, Curtis R. Pickering |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Programmed cell death Gene knockdown biology business.industry Necroptosis Caspase 8 3. Good health Squamous carcinoma 03 medical and health sciences 0302 clinical medicine Cell culture 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Medicine business Caspase 030304 developmental biology |
| DOI: | 10.1101/2020.04.17.039040 |
| Popis: | Caspase-8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCC), and mutations ofCASP8are associated with poor overall survival. The distribution of these mutations in HNSCC suggests that they are likely to be inactivating. Inhibition ofCASP8has been reported to sensitize cancer cells to necroptosis, a unique cell death mechanism. Here, we evaluated howCASP8regulates necroptosis in HSNCC using cell line models and syngeneic mouse xenografts.In vitro, knockdown ofCASP8rendered HNSCCs susceptible to necroptosis induced by a second mitochondria-derived activator of caspase (SMAC) mimetic, Birinapant, when combined with pan-caspase inhibitors Z-VAD-FMK or Emricasan. Strikingly, inhibition ofCASP8function via knockdown or Emricasan treatment was associated with enhanced radiation killing by Birinapant through induction of necroptosis. In a syngeneic mouse model of oral cancer, Birinapant, particularly when combined with radiation delayed tumor growth and enhanced survival underCASP8loss. Exploration of molecular underpinnings of necroptosis sensitivity confirmed that the level of functional receptor-interacting serine/threonine-protein kinase-3 (RIP3), a key enzyme in the necroptosis pathway was crucial in determining susceptibility to this mode of death. Although anin vitroscreen revealed that many HNSCC cell lines were resistant to necroptosis due to low levels of RIP3, patient tumors maintain 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 a relevant therapeutic approach in HNSCC with compromisedCASP8status, provided that RIP3 function is maintained.SignificanceCASP8status regulates necroptotic death in HNSCC and this pathway can be exploited therapeutically. |
| Databáze: | OpenAIRE |
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