Bittner, Sebastian and Knoll, Gertrud and Ehrenschwender, Martin (2017) Hyperosmotic stress enhances cytotoxicity of SMAC mimetics. CELL DEATH & DISEASE, 8: e2967. ISSN 2041-4889,
Full text not available from this repository. (Request a copy)Abstract
Inhibitors of apoptosis (IAP) proteins contribute to cell death resistance in malignancies and emerged as promising targets in cancer therapy. Currently, small molecules mimicking the IAP-antagonizing activity of endogenous second mitochondria-derived activator of caspases (SMAC) are evaluated in phase 1/2 clinical trials. In cancer cells, SMAC mimetic (SM)-mediated IAP depletion induces tumor necrosis factor (TNF) secretion and simultaneously sensitizes for TNF-induced cell death. However, tumor cells lacking SM-induced autocrine TNF release survive and thus limit therapeutic efficacy. Here, we show that hyperosmotic stress boosts SM cytotoxicity in human and murine cells through hypertonicity-induced upregulation of TNF with subsequent induction of apoptosis and/or necroptosis. Hypertonicity allowed robust TNF-dependent killing in SM-treated human acute lymphoblastic leukemia cells, which under isotonic conditions resisted SM treatment due to poor SM-induced TNF secretion. Mechanistically, hypertonicity-triggered TNF release bypassed the dependency on SM-induced TNF production to execute SM cytotoxicity, effectively reducing the role of SM to TNF-sensitizing, but not necessarily TNF-inducing agents. Perspectively, these findings could extend the clinical application of SM.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR-NECROSIS-FACTOR; ALPHA-DEPENDENT APOPTOSIS; KAPPA-B ACTIVATION; TNF-ALPHA; INDUCED NECROPTOSIS; BINDING PROTEIN; CELL-DEATH; L929 CELLS; CANCER; CIAP1; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:16 |
| Last Modified: | 25 Feb 2019 14:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/1418 |
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