The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells

Pokharel, Deep; Padula, Matthew P.; Lu, Jie; Jaiswal, Ritu; Djordjevic, Steven P.; Bebawy, Mary

doi:10.3390/molecules21030290

Cited by 48 publications

(43 citation statements)

References 41 publications

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“…EVs have also been shown to modulate the anti-tumoral response by affecting the immune response, T-cell activation and natural killer cell induction (30)(31)(32)(33). EVs can also contribute to drug resistance via various mechanisms, including the sequestration of drugs (34,35) and the transfer of proteins or RNA (36)(37)(38)(39) (40)(41)(42)(43)(44)(45). The morphology and the proteomic profile of EVs from multi-drug resistant tumours has been shown to be different from those from sensitive tumours (46) and EVs could be used as prognostic and diagnostic biomarkers in cancer (47).…”

mentioning

confidence: 99%

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Samuel

Mulcahy

Furlong

et al. 2017

Phil. Trans. R. Soc. B

105

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Ovarian cancer has a poor overall survival that is partly caused by resistance to drugs such as cisplatin. Resistance can be acquired as a result of changes to the tumour or due to altered interactions within the tumour microenvironment. Extracellular vesicles (EVs), small lipid-bound vesicles that are loaded with macromolecular cargo and released by cells, are emerging as mediators of communication in the tumour microenvironment. We previously showed that EVs mediate the bystander effect, a phenomenon in which stressed cells can communicate with neighbouring naive cells leading to various effects including DNA damage; however, the role of EVs released following cisplatin treatment has not been tested. Here we show that treatment of cells with cisplatin led to the release of EVs that could induce invasion and increased resistance when taken up by bystander cells. This coincided with changes in p38 and JNK signalling, suggesting that these pathways may be involved in mediating the effects. We also show that EV uptake inhibitors could prevent this EV-mediated adaptive response and thus sensitize cells in vitro to the effects of cisplatin. Our results suggest that preventing pro-tumourigenic EV cross-talk during chemotherapy is a potential therapeutic target for improving outcome in ovarian cancer patients. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

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mentioning

confidence: 99%

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Samuel

Mulcahy

Furlong

et al. 2017

Phil. Trans. R. Soc. B

105

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“…Selected differentially regulated protein spots were excised from gels, trypsin digested, and analyzed by LC/MS/MS according to Pokharel et al (2016). Using an autosampler, connected to a nanoLC system (Tempo Eksigent, USA), 10 μL of the sample was loaded at 20 μL/min with MS loading solvent (2% Acetonitrile + 0.2% Trifluoroacetic Acid) onto a C8 trap column (CapTrap.…”

Section: Methodsmentioning

confidence: 99%

Proteome Analysis Reveals Extensive Light Stress-Response Reprogramming in the Seagrass Zostera muelleri (Alismatales, Zosteraceae) Metabolism

et al. 2017

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Seagrasses are marine ecosystem engineers that are currently declining in abundance at an alarming rate due to both natural and anthropogenic disturbances in ecological niches. Despite reports on the morphological and physiological adaptations of seagrasses to extreme environments, little is known of the molecular mechanisms underlying photo-acclimation, and/or tolerance in these marine plants. This study applies the two-dimensional isoelectric focusing (2D-IEF) proteomics approach to identify photo-acclimation/tolerance proteins in the marine seagrass Zostera muelleri. For this, Z. muelleri was exposed for 10 days in laboratory mesocosms to saturating (control, 200 μmol photons m−2 s−1), super-saturating (SSL, 600 μmol photons m−2 s−1), and limited light (LL, 20 μmol photons m−2 s−1) irradiance conditions. Using LC-MS/MS analysis, 93 and 40 protein spots were differentially regulated under SSL and LL conditions, respectively, when compared to the control. In contrast to the LL condition, Z. muelleri robustly tolerated super-saturation light than control conditions, evidenced by their higher relative maximum electron transport rate and minimum saturating irradiance values. Proteomic analyses revealed up-regulation and/or appearances of proteins belonging to the Calvin-Benson and Krebs cycle, glycolysis, the glycine cleavage system of photorespiration, and the antioxidant system. These proteins, together with those from the inter-connected glutamate-proline-GABA pathway, shaped Z. muelleri photosynthesis and growth under SSL conditions. In contrast, the LL condition negatively impacted the metabolic activities of Z. muelleri by down-regulating key metabolic enzymes for photosynthesis and the metabolism of carbohydrates and amino acids, which is consistent with the observation with lower photosynthetic performance under LL condition. This study provides novel insights into the underlying molecular photo-acclimation mechanisms in Z. muelleri, in addition to identifying protein-based biomarkers that could be used as early indicators to detect acute/chronic light stress in seagrasses to monitor seagrass health.

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“…demonstrated Radixin and CD44 are required for regulating P‐gp‐mediated drug efflux in drug resistant breast cancer cells. Moreover, silencing experiments carried out on the recipient cells showed that ERM proteins Ezrin and Moesin are required for the intercellular membrane insertion of P‐gp . Demonstrating for the first time that the intercellular EV‐mediated transfer of P‐gp in the recipient cell is dependent on Ezrin and Moesin, however, functionality is governed by the integrity of the ERM complex (Figure (5)).…”

Section: Proteins Regulating Classical Mdrmentioning

confidence: 99%

Proteins Regulating Microvesicle Biogenesis and Multidrug Resistance in Cancer

Taylor

Bebawy

2019

Proteomics

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Microvesicles (MV) are emerging as important mediators of intercellular communication. While MVs are important signaling vectors for many physiological processes, they are also implicated in cancer pathology and progression. Cellular activation is perhaps the most widely reported initiator of MV biogenesis, however, the precise mechanism remains undefined. Uncovering the proteins involved in regulating MV biogenesis is of interest given their role in the dissemination of deleterious cancer traits. MVs shed from drug‐resistant cancer cells transfer multidrug resistance (MDR) proteins to drug‐sensitive cells and confer the MDR phenotype in a matter of hours. MDR is attributed to the overexpression of ABC transporters, primarily P‐glycoprotein and MRP1. Their expression and functionality is dependent on a number of proteins. In particular, FERM domain proteins have been implicated in supporting the functionality of efflux transporters in drug‐resistant cells and in recipient cells during intercellular transfer by vesicles. Herein, the most recent research on the proteins involved in MV biogenesis and in the dissemination of MV‐mediated MDR are discussed. Attention is drawn to unanswered questions in the literature that may prove to be of benefit in ongoing efforts to improve clinical response to chemotherapy and circumventing MDR.

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The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells

Cited by 48 publications

References 41 publications

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Proteome Analysis Reveals Extensive Light Stress-Response Reprogramming in the Seagrass Zostera muelleri (Alismatales, Zosteraceae) Metabolism

Proteins Regulating Microvesicle Biogenesis and Multidrug Resistance in Cancer

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