Caspase-8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic–induced necroptosis
| Autor: | Kelly Erikson, Curtis R. Pickering, Burak Uzunparmak, Eric Lin, Meng Gao, Jared M. Newton, Jeffrey N. Myers, Heath D. Skinner, Li Wang, Andrew G. Sikora, Antje Lindemann, Mei Zhao, Frederico O. Gleber-Netto, Steven J. Frank |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cell biology Indoles Necroptosis Apoptosis Apoptosis pathways Caspase 8 Mitochondrial Proteins 03 medical and health sciences 0302 clinical medicine Biomimetics Cell Line Tumor Databases Genetic medicine Humans Head and neck cancer Protein kinase A Caspase Gene knockdown biology Squamous Cell Carcinoma of Head and Neck Intracellular Signaling Peptides and Proteins Cancer Dipeptides General Medicine medicine.disease Caspase Inhibitors Head and neck squamous-cell carcinoma Mitochondria Radiation therapy 030104 developmental biology Oncology Caspases 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Medicine Apoptosis Regulatory Proteins Research Article |
| Zdroj: | JCI Insight, Vol 5, Iss 23 (2020) JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | 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. Caspase-8 status sensitizes a murine model of head and neck squamous carcinoma to the combination of radiation and SMAC mimetic treatment through increased necroptosis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|