Phenothiazines alter plasma membrane properties and sensitize cancer cells to injury by inhibiting annexin-mediated repair

Abstract

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. 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. The plasma membrane (PM) shapes and protects cells from the extracellular environment. To keep the PM intact and prevent cell death induced by membrane disruptions, eukaryotic cells have developed efficient repair mechanisms to ensure rapid resealing. Repair strategies depend on both membrane fusion and membrane replacement strategies and involve cytoskeletal and endomembrane systems (1Tang S.K.Y. Marshall W.F. Self-repairing cells: How single cells heal membrane ruptures and restore lost structures.Science. 2017; 356: 1022-1025Crossref PubMed Scopus (55) Google Scholar, 2Andrews N.W. Almeida P.E. Corrotte M. Damage control: Cellular mechanisms of plasma membrane repair.Trends Cell Biol. 2014; 24: 734-742Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 3Bendix P.M. Simonsen A.C. Florentsen C.D. Hager S.C. Mularski A. Zanjani A.A.H. Moreno-Pescador G. Klenow M.B. Sonder S.L. Danielsen H.M. Arastoo M.R. Heitmann A.S. Pandey M.P. Lund F.W. Dias C. et al.Interdisciplinary synergy to reveal mechanisms of annexin-mediated plasma membrane shaping and repair.Cells. 2020; 9: 1029Crossref Scopus (12) Google Scholar). Members of the Annexin (ANXA) protein family (in mammals: ANXA1-11 and ANXA13) are instrumental in coping with PM injuries and are characterized by their Ca2+-dependent binding to anionic phospholipids and ability to aggregate vesicles and fuse membranes (4Gerke V. Creutz C.E. Moss S.E. Annexins: Linking Ca2+ signalling to membrane dynamics.Nat. Rev. Mol. Cell Biol. 2005; 6: 449-461Crossref PubMed Scopus (1077) Google Scholar). Injury to the PM induces a prompt recruitment of ANXAs to the damaged membrane, which is triggered by the influx of extracellular Ca2+ into the cytoplasm and is achieved by binding to negatively charged phospholipids through their C-terminal core domain (5Gerke V. Moss S.E. Annexins: From structure to function.Physiol. Rev. 2002; 82: 331-371Crossref PubMed Scopus (1562) Google Scholar). Although the function of ANXAs in repair has merely been attributed to their ability to aggregate and fuse membranes (6McNeil A.K. Rescher U. Gerke V. McNeil P.L. Requirement for annexin A1 in plasma membrane repair.J. Biol. Chem. 2006; 281: 35202-35207Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar), we and others have recently shown that the strong membrane-shaping and curvature-sensing properties of ANXAs are also critical for repair (7Boye T.L. Jeppesen J.C. Maeda K. Pezeshkian W. Solovyeva V. Nylandsted J. Simonsen A.C. Annexins induce curvature on free-edge membranes displaying distinct morphologies.Sci. Rep. 2018; 8: 10309Crossref PubMed Scopus (43) Google Scholar, 8Boye T.L. Maeda K. Pezeshkian W. Sonder S.L. Haeger S.C. Gerke V. Simonsen A.C. Nylandsted J. Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair.Nat. Commun. 2017; 8: 1623Crossref PubMed Scopus (62) Google Scholar, 9Hakobyan D. Gerke V. Heuer A. Modeling of annexin A2-membrane interactions by molecular dynamics simulations.PLoS One. 2017; 12e0185440Crossref PubMed Scopus (13) Google Scholar). Specifically, ANXA1, ANXA2, and ANXA4-7 are strong inducers of membrane curvature and through a coordinated manipulation of membranes promote PM repair mechanisms (6McNeil A.K. Rescher U. Gerke V. McNeil P.L. Requirement for annexin A1 in plasma membrane repair.J. Biol. Chem. 2006; 281: 35202-35207Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 7Boye T.L. Jeppesen J.C. Maeda K. Pezeshkian W. Solovyeva V. Nylandsted J. Simonsen A.C. Annexins induce curvature on free-edge membranes displaying distinct morphologies.Sci. Rep. 2018; 8: 10309Crossref PubMed Scopus (43) Google Scholar, 8Boye T.L. Maeda K. Pezeshkian W. Sonder S.L. Haeger S.C. Gerke V. Simonsen A.C. Nylandsted J. Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair.Nat. 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J. of with and their in 2006; PubMed Scopus Google Scholar). has cancer for by the trifluoperazine may the of cancer K. induces domain in in charged PubMed Scopus Google Scholar). and to and fusion of and in of from cells and annexin membrane fusion by PubMed Scopus Google Scholar). by we that compromise PM repair by inhibiting function the Using a combination of cell biology, biophysics, and P.M. Simonsen A.C. Florentsen C.D. Hager S.C. Mularski A. Zanjani A.A.H. Moreno-Pescador G. Klenow M.B. Sonder S.L. Danielsen H.M. Arastoo M.R. Heitmann A.S. Pandey M.P. Lund F.W. Dias C. et al.Interdisciplinary synergy to reveal mechanisms of annexin-mediated plasma membrane shaping and repair.Cells. 2020; 9: 1029Crossref Scopus (12) Google Scholar), we that phenothiazines, and in strongly sensitize to membrane by compromising provide that the membrane which membrane in a membrane that is more fragile and prone to ruptures. binding by inhibiting the lateral diffusion of in compromise their ability to and shape membranes, which is for their function during PM repair. a membrane thinning cells to damage and the membrane cell death. To derivatives of sensitize cancer cells to PM cancer cell and by to stress by membrane injury approaches T.L. Maeda K. Pezeshkian W. Sonder S.L. Haeger S.C. Gerke V. Simonsen A.C. Nylandsted J. Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair.Nat. Commun. 2017; 8: 1623Crossref PubMed Scopus (62) Google Scholar, S.L. T.L. R. J. Maeda K. M. Simonsen A.C. Nylandsted J. 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R. by membrane and Rev. 2018; PubMed Scopus Google Scholar). to the repair PM injury with treatment, cells with a in the of the and by cells to repair their PM to by the of cells with to repair and to the cell and sensitize cancer cells to PM damage and compromise the repair the of the ability of phenothiazines, to of in of from cells and annexin membrane fusion by PubMed Scopus Google Scholar), we compromise repair. we to cells and cells to The of in the a repair with injury and repair in more To in membrane by the of in membrane by the to the repair function of To we the recruitment and of ANXAs the damaged membrane injury. cells with to and by during injury. cells with to the PM to of in cells to and to of the cells by the damaged membrane to in to to in cells and the of recruitment to the membrane the of the in the which may negatively the repair show that the of the that derivatives may compromise To the of on function the membrane, we of a membrane of membrane on a membrane of a The from the and for shape by which on the membrane and on the of membrane in P.M. Simonsen A.C. Florentsen C.D. Hager S.C. Mularski A. Zanjani A.A.H. Moreno-Pescador G. Klenow M.B. Sonder S.L. Danielsen H.M. Arastoo M.R. Heitmann A.S. Pandey M.P. Lund F.W. Dias C. et al.Interdisciplinary synergy to reveal mechanisms of annexin-mediated plasma membrane shaping and repair.Cells. 2020; 9: 1029Crossref Scopus (12) Google Scholar, 8Boye T.L. Maeda K. Pezeshkian W. Sonder S.L. Haeger S.C. Gerke V. Simonsen A.C. Nylandsted J. Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair.Nat. Commun. 2017; 8: 1623Crossref PubMed Scopus (62) Google Scholar). is for the PM the injury to the that a membrane of proteins to anionic membrane in the of of the into and a of and and have that of (7Boye T.L. Jeppesen J.C. Maeda K. Pezeshkian W. Solovyeva V. Nylandsted J. Simonsen A.C. Annexins induce curvature on free-edge membranes displaying distinct morphologies.Sci. Rep. 2018; 8: 10309Crossref PubMed Scopus (43) Google Scholar, 8Boye T.L. Maeda K. Pezeshkian W. Sonder S.L. Haeger S.C. Gerke V. Simonsen A.C. Nylandsted J. Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair.Nat. Commun. 2017; 8: 1623Crossref PubMed Scopus (62) Google Scholar). The of membrane to induced strong curvature and membrane from the (7Boye T.L. Jeppesen J.C. Maeda K. Pezeshkian W. Solovyeva V. Nylandsted J. Simonsen A.C. Annexins induce curvature on free-edge membranes displaying distinct morphologies.Sci. Rep. 2018; 8: 10309Crossref PubMed Scopus (43) Google Scholar, 8Boye T.L. Maeda K. Pezeshkian W. Sonder S.L. Haeger S.C. Gerke V. Simonsen A.C. Nylandsted J. Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair.Nat. Commun. 2017; 8: 1623Crossref PubMed Scopus (62) Google and of the in the that and with binding of ANXAs to the the protein into the membrane by the strong from of curvature and membrane shaping for ANXA1, ANXA2, and and also and binding to the membrane ANXAs to the through the that on the membrane-shaping of ANXAs to binding to membrane To into the of on the biophysical properties of the membrane, we membrane with of and and the by Here, induced a of membrane that it into membranes and the of to on the of a The bilayer, by to and to to induced membrane and in the bilayer, the and for membrane to and of a in membrane in a we show that membrane and membrane in with D. by the of PubMed Scopus Google Scholar, J. 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Full Text Full Text PDF PubMed Scopus Google Scholar). Specifically, we the for biophysical membrane binding to the membrane on anionic we the systems to the lateral diffusion for in the The reveal that the lateral diffusion of in the membrane, which that the of in the membrane is in membranes, it binding by the diffusion of and binding the show that ANXA2, induces curvature on a is to the to a membrane, the lateral diffusion of is which the has a curvature in the of and shape into membrane it the membrane making it more in with the Our results that derivatives of sensitize cancer cells to PM injuries. a of repair, cells are more to both and PM provide that repair by the biophysical properties of the membrane, which has on the membrane-shaping of proteins during repair. the of on cell damage may to membrane C. A.C. A. Nylandsted J. J. A. K. S. M. for cancer 9: Full Text Full Text PDF PubMed Scopus Google Scholar, M. S. D. A. D. C. 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Annexin A4 are by membrane in plasma membrane PubMed Google Scholar). the membrane-shaping function of ANXAs P.M. Simonsen A.C. Florentsen C.D. Hager S.C. Mularski A. Zanjani A.A.H. Moreno-Pescador G. Klenow M.B. Sonder S.L. Danielsen H.M. Arastoo M.R. Heitmann A.S. Pandey M.P. Lund F.W. Dias C. et al.Interdisciplinary synergy to reveal mechanisms of annexin-mediated plasma membrane shaping and repair.Cells. 2020; 9: 1029Crossref Scopus (12) Google Scholar, 7Boye T.L. Jeppesen J.C. Maeda K. Pezeshkian W. Solovyeva V. Nylandsted J. Simonsen A.C. Annexins induce curvature on free-edge membranes displaying distinct morphologies.Sci. Rep. 2018; 8: 10309Crossref PubMed Scopus (43) Google Scholar, 8Boye T.L. Maeda K. Pezeshkian W. Sonder S.L. Haeger S.C. Gerke V. Simonsen A.C. Nylandsted J. Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair.Nat. Commun. 2017; 8: 1623Crossref PubMed Scopus (62) Google Scholar, S.L. T.L. R. J. Maeda K. M. Simonsen A.C. Nylandsted J. Annexin is for plasma membrane Rep. 9: PubMed Scopus Google Scholar, M. Gerke V. and membrane induced by the membrane binding protein annexin Biol. Chem. Full Text Full Text PDF PubMed Scopus Google is by which results in PM repair injury. a thinning of the the membrane more prone to which in are the is and derivatives of to by the repair function the cells from and cells in with from cancer and cells from in with in a of in with and in a of by with a of of of The injury with a with a The cells to injury and to injury. to of repair by of a in during the of to the for of and cells and protein cells in with protein for to the cells to and with in for To membrane and cell cells with and and and in with in with for by for to and for to repair. with for by on a for to a a of in the cell in with by for with the of of W. Cell death by with with a C-terminal from to the ANXAs and (7Boye T.L. Jeppesen J.C. Maeda K. Pezeshkian W. Solovyeva V. Nylandsted J. Simonsen A.C. Annexins induce curvature on free-edge membranes displaying distinct morphologies.Sci. Rep. 2018; 8: 10309Crossref PubMed Scopus (43) Google Scholar, 8Boye T.L. Maeda K. Pezeshkian W. Sonder S.L. Haeger S.C. Gerke V. Simonsen A.C. Nylandsted J. Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair.Nat. Commun. 2017; 8: 1623Crossref PubMed Scopus (62) Google Scholar). into the from and with and with a and a cells for the of and the induced by and by proteins with The and domain of by by and on a and by and to of and from a and of the to the and on a for and in a for to to ensure of the The in for the with for to on of a The membranes to and for to The of ANXAs and with membrane with membrane a with a and a for and proteins in a of to the cell from a with a of and the to on the of the ANXAs to by the of the of The from and to and membrane The by a of with and ANXAs with the The membrane to (7Boye T.L. Jeppesen J.C. Maeda K. Pezeshkian W. Solovyeva V. 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