Hyperosmotic stress enhances cytotoxicity of SMAC mimetics
Sebastian Bittner1, Gertrud Knoll1, Martin Ehrenschwender1
1Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg 93053, Germany.
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.
Insights
Hyperosmotic stress enhances cancer cell killing by SMAC mimetics (SM) by increasing TNF. This approach overcomes resistance in cancer cells that do not produce enough TNF, improving SM efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Pathways
Background:
- Inhibitors of apoptosis (IAP) proteins promote cancer cell survival.
- SMAC mimetics (SM) are investigated as cancer therapeutics by antagonizing IAPs.
- SM induce tumor necrosis factor (TNF) secretion and sensitize cells to TNF, but resistance occurs when tumor cells lack SM-induced TNF.
Purpose of the Study:
- To investigate if hyperosmotic stress can enhance SM cytotoxicity in cancer cells.
- To elucidate the mechanism by which hyperosmotic stress affects SM efficacy.
- To overcome therapeutic resistance to SM in cancer treatment.
Main Methods:
- Treatment of human and murine cancer cells with SMAC mimetics (SM) and hyperosmotic stress.
- Analysis of TNF secretion, apoptosis, and necroptosis induction.
- Comparison of cell killing under isotonic and hypertonic conditions.
Main Results:
- Hyperosmotic stress significantly boosts SM-induced cytotoxicity in various cancer cells.
- Hypertonicity upregulates TNF production, leading to apoptosis and/or necroptosis.
- This strategy effectively kills cancer cells resistant to SM due to poor TNF secretion.
Conclusions:
- Hyperosmotic stress is a potent enhancer of SMAC mimetic therapy.
- Hypertonicity-induced TNF production bypasses the need for SM-induced TNF secretion for cytotoxicity.
- This approach broadens the potential clinical application of SMAC mimetics in cancer treatment.
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