Identification of novel macropinocytosis inhibitors using a rational screen of Food and Drug Administration‐approved drugs

Lin, Hui Ping; Singla, Bhupesh; Ghoshal, Pushpankur; Faulkner, Jessica; Cherian‐Shaw, Mary; O’Connor, Paul; She, Jin Xiong; Chantemèle, Eric J. Belin de; Csányi, Gábor

doi:10.1111/bph.14429

Cited by 98 publications

(93 citation statements)

References 60 publications

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“…Identification of novel molecular machinery regulating macropinocytosis will aid future studies and may pave the way to specifically modulate macropinocytosis in vitro and in vivo. With the application of small-molecule inhibitors [55], siRNA libraries [120] and CRISPR libraries, there are exciting opportunities for high-throughput screens to be performed to identify novel macropinocytosis regulators. Ultimately, a greater understanding of the different pathways of macropinocytosis in different cell types will provide the potential to modulate individual functions which are regulated by these endocytic pathways.…”

Section: Resultsmentioning

confidence: 99%

“…Our understanding of the different pathways of macropinocytosis, such as constitutive versus growth factor-induced macropinocytosis, and dorsal versus peripheral ruffling pathways of macropinocytosis, largely result from the studies using macrophages. Macrophages from a variety sources have been used to study macropinocytosis, in particular primary mouse bone marrow-derived macrophages (BMDMs) [9,17], primary mouse peritoneal macrophages [17], the macrophage cell line RAW 264.7 [54,55] and human monocyte-derived macrophages (hMDMs) [45,56].…”

Section: Macrophagesmentioning

confidence: 99%

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Macropinocytosis in Different Cell Types: Similarities and Differences

2020

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Macropinocytosis is a unique pathway of endocytosis characterised by the nonspecific internalisation of large amounts of extracellular fluid, solutes and membrane in large endocytic vesicles known as macropinosomes. Macropinocytosis is important in a range of physiological processes, including antigen presentation, nutrient sensing, recycling of plasma proteins, migration and signalling. It has become apparent in recent years from the study of specialised cells that there are multiple pathways of macropinocytosis utilised by different cell types, and some of these pathways are triggered by different stimuli. Understanding the physiological function of macropinocytosis requires knowledge of the regulation and fate of the macropinocytosis pathways in a range of cell types. Here, we compare the mechanisms of macropinocytosis in different primary and immortalised cells, identify the gaps in knowledge in the field and discuss the potential approaches to analyse the function of macropinocytosis in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Macrophagesmentioning

confidence: 99%

Macropinocytosis in Different Cell Types: Similarities and Differences

2020

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“…Among nonclathrinmediated endocytic processes, macropi nocytosis mediates the uptake of nutrients and extracellular flu id into cells (35). However, neither EIPA, an amiloride derivative inhibiting Na + /H + exchange needed for macropinosome matura tion (36), nor imipramine, a newly identified selective inhibitor of macropinocytosis (37), interfered with antibody transfer (Figure 8, E and F, and Supplemental Figure 6, E-H). Since many endocytosis routes are dynamin dependent, we tested the effect of dynamin inhibitors on the transfer of anti bodies.…”

Section: Resultsmentioning

confidence: 99%

Transcytosis route mediates rapid delivery of intact antibodies to draining lymph nodes

Kähäri¹,

Fair-Mäkelä²,

Auvinen³

et al. 2019

Journal of Clinical Investigation

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“…As shown in Figure A,B, a substantial part of the biotinylated claudin‐1 was resistant to stripping, which is a biochemical demonstration of the endocytosis of claudin‐1 in SAS cells. In addition, endocytosis of claudin‐1 in SAS cells was investigated in the presence of an inhibitor of clathrin‐dependent endocytosis, CPZ, and an inhibitor of macropinocytosis, IMP . Addition of IMP decreased the extent of stripping‐resistant claudin‐1, suggesting that IMP inhibited claudin‐1 endocytosis.…”

Section: Resultsmentioning

confidence: 99%

Intracellular claudin‐1 at the invasive front of tongue squamous cell carcinoma is associated with lymph node metastasis

et al. 2019

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractClaudins are the major component of tight junctions, which form a primary barrier to paracellular diffusion and maintain cell polarity in normal epithelia and endothelia. In cancer cells, claudins play additional roles besides serving as components of the tight junctions, and participate in anoikis or invasion. Among the claudin family proteins, claudin-1 has the most promising potential, both diagnostically and prognostically, in many types of cancers, including oral, gastric, liver, and colon cancers.However, conflicting results have been reported in relation to the degree of claudin-1 expression and the prognosis, suggesting that the expression level of claudin-1 alone is not sufficient to analyze the relationship between claudin-1 and cancer progression. As endocytic trafficking of claudin-1 has been reported in several epithelial cell types in vitro, we aimed to determine whether intracellular localization of claudin-1 is the missing aspect between claudin-1 and cancer. We investigated the expression of claudin-1 in 83 tongue squamous cell carcinoma (TSCC) pathological specimens.Although the expression level of claudin-1 based on immunohistochemistry was not associated with TSCC progression, within the high claudin-1 expression group, the incidence of intracellular localization of claudin-1 was correlated with cervical lymph node metastasis. In an in vitro experiment, claudin-1 was constitutively internalized in TSCC-derived cells. Motility of TSCC-derived cells was increased by deficiency of claudin-1, suggesting that the decrease in cell-surface claudin-1 promoted the cell migration. Therefore, intracellular localization of claudin-1 at the invasion front may represent a promising diagnostic marker of TSCC. K E Y W O R D Sclaudin-1, endocytosis, invasion front, metastasis, tongue squamous cell carcinoma

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Identification of novel macropinocytosis inhibitors using a rational screen of Food and Drug Administration‐approved drugs

Abstract: Our results identify imipramine as a new pharmacological tool to study macropinocytosis in cellular and biological systems. This study also suggests that imipramine could be a good candidate for repurposing as a therapeutic agent in pathological processes involving macropinocytosis.

Cited by 98 publications

References 60 publications

Macropinocytosis in Different Cell Types: Similarities and Differences

Macropinocytosis in Different Cell Types: Similarities and Differences

Transcytosis route mediates rapid delivery of intact antibodies to draining lymph nodes

Intracellular claudin‐1 at the invasive front of tongue squamous cell carcinoma is associated with lymph node metastasis

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