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

Heitmann, Anne Sofie Busk; Zanjani, Ali Asghar Hakami; Klenow, Martin Berg; Mularski, Anna; Sønder, Stine Lauritzen; Lund, Frederik Wendelboe; Boye, Theresa Louise; Dias, Catarina; Bendix, Poul Martin; Simonsen, Adam Cohen; Khandelia, Himanshu; Nylandsted, Jesper

doi:10.1016/j.jbc.2021.101012

Cited by 20 publications

(22 citation statements)

References 73 publications

(115 reference statements)

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“…To combat these stresses, cells of all sizes have developed robust wound repair mechanisms to alleviate the chances of infection or death [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Cell wound repair is highly conserved and a variety of model organisms and systems have been developed to study this process, including the Drosophila syncytial embryo [ 9 ], Xenopus oocytes [ 10 , 11 ], Dictyostelium [ 12 ], sea urchin eggs [ 13 ], C. elegans [ 14 ], and tissue culture cells [ 15 , 16 ]. These have proven to be excellent and complementary systems for studying this dynamic cell biological process and for identifying the molecular players/pathways involved.…”

Section: Introductionmentioning

confidence: 99%

Wrangling Actin Assemblies: Actin Ring Dynamics during Cell Wound Repair

Hui

Stjepić

Nakamura

et al. 2022

Cells

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To cope with continuous physiological and environmental stresses, cells of all sizes require an effective wound repair process to seal breaches to their cortex. Once a wound is recognized, the cell must rapidly plug the injury site, reorganize the cytoskeleton and the membrane to pull the wound closed, and finally remodel the cortex to return to homeostasis. Complementary studies using various model organisms have demonstrated the importance and complexity behind the formation and translocation of an actin ring at the wound periphery during the repair process. Proteins such as actin nucleators, actin bundling factors, actin-plasma membrane anchors, and disassembly factors are needed to regulate actin ring dynamics spatially and temporally. Notably, Rho family GTPases have been implicated throughout the repair process, whereas other proteins are required during specific phases. Interestingly, although different models share a similar set of recruited proteins, the way in which they use them to pull the wound closed can differ. Here, we describe what is currently known about the formation, translocation, and remodeling of the actin ring during the cell wound repair process in model organisms, as well as the overall impact of cell wound repair on daily events and its importance to our understanding of certain diseases and the development of therapeutic delivery modalities.

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Section: Introductionmentioning

confidence: 99%

Wrangling Actin Assemblies: Actin Ring Dynamics during Cell Wound Repair

Hui

Stjepić

Nakamura

et al. 2022

Cells

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“…An alternative to antibody therapy would be to use small molecule inhibitors or peptides. Drugs used to treat psychiatric and allergic conditions, such as trifluoperazine, have been reported to inhibit annexin-mediated membrane repair 32 , and a synthetic cell-penetrating peptide that interacts with ANXA2 has been shown to reduce metastasis to murine lungs 33 . Major compressive and shearing forces are encountered during invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the membrane repair protein annexin-A2 prevents tumour invasion and metastasis

Gounou

Bouvet²,

d'Agata

et al. 2022

Preprint

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Cancer cells are exposed to major compressive and shearing forces during invasion and metastasis, leading to extensive plasma membrane damage. To survive this mechanical stress, they need to repair membrane injury efficiently. Targeting the membrane repair machinery is thus potentially a new way to prevent invasion and metastasis. We show here that annexin-A2 (ANXA2) is required for membrane repair in MDA-MB-231 cells, a highly invasive triple-negative breast cancer cell line. Mechanistically, we show by fluorescence and electron microscopy that cells fail to reseal membrane damaged by shear stress when ANXA2 is silenced or the protein is inhibited with neutralizing antibody. Silencing of ANXA2 has no effect on proliferation in vitro, and even accelerates migration in wound healing assays, but reduces tumor cell dissemination in both mice and zebrafish. We show that high expression of ANXA2 predicts poor prognosis in high-grade lung, ovarian, gastric and breast cancers. We expect that inhibiting membrane repair will be particularly effective in these aggressive, poor prognosis tumors because they rely on the membrane repair machinery to survive membrane damage during tumor invasion and metastasis. This could be achieved either with monoclonal anti-ANXA2 antibodies, which have been shown to inhibit metastasis of MDA-MB-231 cells, or with small molecule drugs.

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“…A recent study found that phenothiazine derivatives, especially trifluoperazine (TFP), are able to inhibit the repair function of ANXA proteins at the cell membrane. TFP delays the accumulation of ANXA2-GFP at the damaged plasma membrane, inhibits ANXA-mediated membrane curvature, affects the membrane-forming ability of ANXA and, to some extent, impairs ANXA proteins from binding to membrane patches (Table 3) (Heitmann et al, 2021). Not only inhibitors, but also their functions need deeper investigation.…”

Section: The Inhibitors Of the Anxa Protein Familymentioning

confidence: 99%

Annexin A protein family: Focusing on the occurrence, progression and treatment of cancer

Zhang

Guo

et al. 2023

Front. Cell Dev. Biol.

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The annexin A (ANXA) protein family is a well-known tissue-specific multigene family that encodes Ca2+ phospholipid-binding proteins. A considerable amount of literature is available on the abnormal expression of ANXA proteins in various malignant diseases, including cancer, atherosclerosis and diabetes. As critical regulatory molecules in cancer, ANXA proteins play an essential role in cancer progression, proliferation, invasion and metastasis. Recent studies about their structure, biological properties and functions in different types of cancers are briefly summarised in this review. We further discuss the use of ANXA as new class of targets in the clinical diagnosis and treatment of cancer.

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

Cited by 20 publications

References 73 publications

Wrangling Actin Assemblies: Actin Ring Dynamics during Cell Wound Repair

Wrangling Actin Assemblies: Actin Ring Dynamics during Cell Wound Repair

Inhibition of the membrane repair protein annexin-A2 prevents tumour invasion and metastasis

Annexin A protein family: Focusing on the occurrence, progression and treatment of cancer

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