Heimer, Sina and Knoll, Gertrud and Neubert, Patrick and Hammer, Karin P. and Wagner, Stefan and Bauer, Richard J. and Jantsch, Jonathan and Ehrenschwender, Martin (2021) Hypertonicity counteracts MCL-1 and renders BCL-XL a synthetic lethal target in head and neck cancer. FEBS JOURNAL, 288 (6). pp. 1822-1838. ISSN 1742-464X, 1742-4658
Full text not available from this repository. (Request a copy)Abstract
Head and neck squamous cell carcinoma (HNSCC) is an aggressive and difficult-to-treat cancer entity. Current therapies ultimately aim to activate the mitochondria-controlled (intrinsic) apoptosis pathway, but complex alterations in intracellular signaling cascades and the extracellular microenvironment hamper treatment response. On the one hand, proteins of the BCL-2 family set the threshold for cell death induction and prevent accidental cellular suicide. On the other hand, controlling a cell's readiness to die also determines whether malignant cells are sensitive or resistant to anticancer treatments. Here, we show that HNSCC cells upregulate the proapoptotic BH3-only protein NOXA in response to hyperosmotic stress. Induction of NOXA is sufficient to counteract the antiapoptotic properties of MCL-1 and switches HNSCC cells from dual BCL-XL/MCL-1 protection to exclusive BCL-XL addiction. Hypertonicity-induced functional loss of MCL-1 renders BCL-XL a synthetically lethal target in HNSCC, and inhibition of BCL-XL efficiently kills HNSCC cells that poorly respond to conventional therapies. We identify hypertonicity-induced upregulation of NOXA as link between osmotic pressure in the tumor environment and mitochondrial priming, which could perspectively be exploited to boost efficacy of anticancer drugs.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HYPEROSMOTIC STRESS; CELLS; EXPRESSION; CALCIUM; INHIBITOR; CHANNELS; NOXA; INDUCTION; APOPTOSIS; DESIGN; BCL-XL; head and neck cancer; hyperosmotic stress; MCL-1; NOXA |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene Medicine > Lehrstuhl für Mund-, Kiefer- und Gesichtschirurgie |
| Depositing User: | Petra Gürster |
| Date Deposited: | 15 Apr 2021 07:45 |
| Last Modified: | 15 Apr 2021 07:45 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44064 |
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