Phenothiazines alter plasma membrane properties and sensitize cancer cells to injury by inhibiting annexin-mediated repair
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- Phenothiazines alter plasma membrane properties and sensitize cancer cells to injury by inhibiting annexin-mediated repair
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Repair of damaged plasma membrane in eukaryotic cells is largely dependent on the binding of annexin repair proteins to phospholipids. Changing the biophysical properties of the plasma membrane may provide means to compromise annexin-mediated repair and sensitize cells to injury. Since, cancer cells experience heightened membrane stress and are more dependent on efficient plasma membrane repair, inhibiting repair may provide approaches to sensitize cancer cells to plasma membrane damage and cell death. Here, we show that derivatives of phenothiazines, which have widespread use in the fields of psychiatry and allergy treatment, strongly sensitize cancer cells to mechanical-, chemical-, and heat-induced injury by inhibiting annexin-mediated plasma membrane repair. Using a combination of cell biology, biophysics, and computer simulations, we show that trifluoperazine acts by thinning the membrane bilayer, making it more fragile and prone to ruptures. Secondly, it decreases annexin binding by compromising the lateral diffusion of phosphatidylserine, inhibiting the ability of annexins to curve and shape membranes, which is essential for their function in plasma membrane repair. Our results reveal a novel avenue to target cancer cells by compromising plasma membrane repair in combination with noninvasive approaches that induce membrane injuries.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 101012 |
| Tidsskrift | Journal of Biological Chemistry |
| Vol/bind | 297 |
| Udgave nummer | 2 |
| ISSN | 0021-9258 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
This study was supported by the Novo Nordisk Foundation Interdisciplinary Synergy Grant (NNF18OC0034936), the Danish Council for Independent Research Natural Sciences (9040-00252B), and Scientific Committee Danish Cancer Society (R90-A5847-14-S2). The simulations were carried out on the Danish e-Infrastructure Cooperation National HPC Center, on ABACUS 2.0 at the University of Southern Denmark, SDU, and on computing resources on the Swiss cluster Piz Daint as part of a PRACE project (grant number 2016153468). We also acknowledge that the results of this research have been achieved using the DECI resource Kay based in Ireland at ICHEC with support from the PRACE aisbl. Part of the computations was carried out on the ROBUST resource for Biomolecular simulations with support from the Novo Nordisk Foundation.
Funding Information:
Acknowledgments—This study was supported by the Novo Nordisk Foundation Interdisciplinary Synergy Grant (NNF18OC0034936), the Danish Council for Independent Research Natural Sciences (9040-00252B), and Scientific Committee Danish Cancer Society (R90-A5847-14-S2). The simulations were carried out on the Danish e-Infrastructure Cooperation National HPC Center, on ABACUS 2.0 at the University of Southern Denmark, SDU, and on computing resources on the Swiss cluster Piz Daint as part of a PRACE project (grant number 2016153468). We also acknowledge that the results of this research have been achieved using the DECI resource Kay based in Ireland at ICHEC with support from the PRACE aisbl. Part of the computations was carried out on the ROBUST resource for Biomolecular simulations with support from the Novo Nordisk Foundation.
Publisher Copyright:
© 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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