scholarly journals Focused ultrasound stimulates ER localized mechanosensitive PANNEXIN-1 to mediate intracellular calcium release in invasive cancer cells

2020 ◽  
Author(s):  
Nan Sook Lee ◽  
Chi Woo Yoon ◽  
Qing Wang ◽  
Sunho Moon ◽  
Kweon Mo Koo ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Calcium Signaling ◽  
Cancer Cells ◽  
Focused Ultrasound ◽  
Calcium Release ◽  
Atp Release ◽  
Invasive Cancer ◽  
Great Promise ◽  
Pannexin 1 ◽  
Cellular Processes

ABSTRACTFocused ultrasound (FUS) is a rapidly developing stimulus technology with the potential to uncover novel mechanosensory dependent cellular processes. Since it is noninvasive, it holds great promise for future therapeutic applications in patients used either alone or as a complement to boost existing treatments. For example, FUS stimulation causes invasive but not noninvasive cancer cell lines to exhibit marked activation of calcium signaling pathways. Here, we identify the membrane channel PANNEXIN1 (PANX1) as a mediator for activation of calcium signaling in invasive cancer cells. Knockdown of PANX1 decreases calcium signaling in invasive cells, while PANX1 overexpression enhances calcium elevations in non-invasive cancer cells. We demonstrate that FUS may directly stimulate mechanosensory PANX1 localized in endoplasmic reticulum to evoke calcium release from internal stores. This process does not depend on mechanosensory stimulus transduction through an intact cytoskeleton and does not depend on plasma membrane localized PANX1. Plasma membrane localized PANX1 however plays a different role in mediating the spread of intercellular calcium waves via ATP release. Additionally, we show that FUS stimulation evokes cytokine/chemokine release from invasive cancer cells, suggesting that FUS could be an important new adjuvant treatment to improve cancer immunotherapy.

scholarly journals TMEM110 regulates the maintenance and remodeling of mammalian ER–plasma membrane junctions competent for STIM–ORAI signaling

2015 ◽  
Vol 112 (51) ◽  
pp. E7083-E7092 ◽  
Author(s):  
Ariel Quintana ◽  
Vangipurapu Rajanikanth ◽  
Suzette Farber-Katz ◽  
Aparna Gudlur ◽  
Chen Zhang ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Calcium Signaling ◽  
Mammalian Cells ◽  
Calcium Release ◽  
Close Contact ◽  
Transmembrane Protein ◽  
Regulatory Protein ◽  
Major Mechanism ◽  
Genome Wide ◽  
Core Elements

The stromal interaction molecule (STIM)–ORAI calcium release-activated calcium modulator (ORAI) pathway controls store-dependent calcium entry, a major mechanism of physiological calcium signaling in mammalian cells. The core elements of the pathway are the regulatory protein STIM1, located in the endoplasmic reticulum (ER) membrane, the calcium channel ORAI1 in the plasma membrane, and sites of close contact between the ER and the plasma membrane that permit the two proteins to interact. Research on calcium signaling has centered on STIM1, ORAI1, and a few proteins that directly modulate STIM–ORAI function. However, little is known about proteins that organize ER–plasma membrane junctions for STIM–ORAI-dependent calcium signaling. Here, we report that an ER-resident membrane protein identified in a previous genome-wide RNAi screen, transmembrane protein 110 (TMEM110), regulates the long-term maintenance of ER–plasma membrane junctions and the short-term physiological remodeling of the junctions during store-dependent calcium signaling.

scholarly journals Defective membrane repair machinery impairs survival of invasive cancer cells

2020 ◽  
Author(s):  
F. Bouvet ◽  
M. Ros ◽  
E. Bonedeau ◽  
C. Croissant ◽  
L. Frelin ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Invasive Cancer ◽  
Migration And Invasion ◽  
High Survival ◽  
Membrane Repair ◽  
Membrane Injury ◽  
Promising Avenue

AbstractCancer cells are able to reach distant tissues by migration and invasion processes. Enhanced ability to cope with physical stresses leading to cell membrane damages may offer to cancer cells high survival rate during metastasis. Consequently, down-regulation of the membrane repair machinery may be a therapeutic avenue for inhibiting metastasis. We show that migration of MDA-MB-231 cells on collagen I fibrils induces disruptions of plasma membrane and pullout of membrane fragments in the wake of cells. These cells are able to reseal membrane damages thanks to annexins (Anx) that are highly expressed in invasive cancer cells. In vitro membrane repair assays reveal that MDA-MB-231 cells respond heterogeneously to membrane injury and some of them possess very efficient repair machinery. Finally, we show that silencing of AnxA5 and AnxA6 leads to major defect of the membrane repair machinery responsible for the death of migrating MDA-MB-231 cells. Inhibition of membrane repair machinery may therefore represent a promising avenue for annihilating cancer metastasis.SummaryCancer cells are able to reach distant tissues by migration and invasion processes. This study shows that inhibition of the plasma membrane repair machinery may represent a promising avenue for annihilating cancer metastasis.

scholarly journals The phospholipase D inhibitor FIPI potently blocks EGF-induced calcium signaling in human breast cancer cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Helena M. Stricker ◽  
Nadine Rommerswinkel ◽  
Silvia Keil ◽  
Sandina A. Gnoth ◽  
Bernd Niggemann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Calcium Signaling ◽  
Cancer Cells ◽  
Phospholipase D ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Calcium Release ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Expression Levels

Abstract Background Phosphotyrosine kinase (PTK)-mediated phospholipase C-γ1 (PLC-γ1) signaling plays a crucial role in the release of the universal second messenger calcium from intracellular stores, which is mandatory for several cellular processes, including cell migration. However, PLC-γ1 could also be activated in a PTK-independent manner by phospholipase D (PLD)-derived phosphatidic acid (PA). Because both higher PLD expression levels and PLD activity have also been associated with breast cancer cell invasion and migration, we wondered whether there might be a link between PLD and PLC-γ1, which was investigated in this study. Materials MDA-MB-468-NEO (EGFR positive) and MDA-MB-468-HER2 (EGFR and HER2 positive) human breast cancer cells were used in this study. The migratory behavior of the cells in the presence of epidermal growth factor (EGF) and the PLD inhibitor 5-fluoro-2-indolyl-des-chlorohalopemide (FIPI) was analyzed using the 3D collagen matrix migration assay. Changes in cytosolic calcium levels in the presence of EGF, FIPI and Sig-1R agonists and antagonists as well as in PLD1 siRNA knockdown cells were determined by flow cytometry. Western blot analyses were performed to determine the basal expression levels and phosphorylation patterns of EGFR, HER2, AKT, MAPKp42/44, PLC-γ1 and Sig-1R. Results The EGF-induced migration of MDA-MB-468-NEO and MDA-MB-468-HER2 cells was significantly impaired by FIPI. Likewise, FIPI also significantly abolished EGF-induced calcium release in both cell lines. However, neither the expression levels nor the phosphorylation patterns of EGFR, HER2, AKT, MAPKp42/44 and PLC-γ1 were markedly changed by FIPI. Knockdown of PLD1 expression by siRNA also significantly impaired EGF-induced calcium release in both cell lines. Targeting Sig-1R, which interacts with IP3R, with the antagonist BD1047 also abrogated EGF-induced calcium release. However, EGF-induced calcium release was also impaired if cells were treated with the Sig-1R agonists PRE084 and PPBP maleate. Conclusion In summary, blocking PLD activity with the specific inhibitor FIPI or knocking down PDL1 expression by siRNA significantly impaired EGF-induced calcium release in MDA-MB-468-NEO and MDA-MB-468-HER2 cells, likely indicating a connection between PLD activity and PLC-γ1-mediated calcium signaling. However, how PLD activity interferes with the release of calcium from intracellular stores remains unclear.

scholarly journals Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

2019 ◽  
Author(s):  
Yang Yang ◽  
Leon Delalio ◽  
Angela K Best ◽  
Edgar Macal ◽  
Jenna Milstein ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Cells ◽  
Plasma Membrane ◽  
Intracellular Calcium ◽  
Tumor Necrosis ◽  
Purinergic Signaling ◽  
Flow Cytometric Analysis ◽  
Atp Release ◽  
Pannexin 1 ◽  
Intracellular Ca

In BriefInterleukine-1 beta (IL-1β) has been identified as a critical factor that contributes to the inflammatory response in cardiovascular disease (e.g., atherosclerosis). Pannexin 1 (Panx1) channel activity in endothelial cells regulates localized inflammatory cell recruitment. In response to prolonged tumor necrosis factor alpha (TNF) treatment, Yang et al. found that the Panx1 channel is targeted to the plasma membrane, where it facilitates an increase in intracellular calcium to control the production and release of cytokines including IL-1β.GRAPHICAL ABSTRACTAbstractThe proinflammatory cytokine IL-1β is a significant risk factor in cardiovascular disease that can be targeted to reduce major cardiovascular events. IL-1β expression and release are tightly controlled by changes in intracellular Ca2+. In addition, purinergic signaling through ATP release has also been reported to promote IL-1β production. Despite this, the mechanisms that control IL-1β synthesis and expression have not been identified. The pannexin 1 (Panx1) channel has canonically been implicated in ATP release, especially during inflammation. However, resolution of purinergic signaling occurs quickly due to blood flow and the presence of ectonucleotidases. We examined Panx1 in human endothelial cells following treatment with the pro-inflammatory cytokine tumor necrosis alpha (TNF). In response to long-term TNF treatment, we identified a dramatic increase in Panx1 protein expression at the plasma membrane. Analysis by whole transcriptome sequencing (RNA-seq), qPCR, and treatment with specific kinase inhibitors, revealed that TNF signaling induced NFκβ-associated Panx1 transcription. Genetic inhibition of Panx1 reduced the expression and secretion of IL-1β. We initially hypothesized that increased Panx1-mediated ATP release acted in a paracrine fashion to control cytokine expression. However, our data demonstrate that IL1-β expression was not altered after direct ATP stimulation, following degradation of ATP by apyrase, or after pharmacological blockade of P2 receptors. These data suggest that non-purinergic pathways, involving Panx1, control IL-1β production. Because Panx1 forms a large pore channel, we hypothesized it may act to passively diffuse Ca2+ into the cell upon opening to regulate IL-1β. High-throughput flow cytometric analysis demonstrated that TNF treatments lead to elevated intracellular Ca2+. Genetic or pharmacological inhibition of Panx1 reduced TNF-associated increases in intracellular Ca2+, and IL-1β transcription. Furthermore, we found that the Ca2+-sensitive NFκβ-p65 protein failed to localize to the nucleus after genetic or pharmacological block of Panx1. Taken together, our study provides the first evidence that intracellular Ca2+ regulation via the Panx1 channel induces a feed-forward effect on NFκβ to regulate IL-1β synthesis and release in endothelium during inflammation.

scholarly journals S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Jyoti K. Jaiswal ◽  
Stine P. Lauritzen ◽  
Luana Scheffer ◽  
Masakiyo Sakaguchi ◽  
Jakob Bunkenborg ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cancer Cells ◽  
Invasive Cancer ◽  
Membrane Repair ◽  
Plasma Membrane Repair

vitreal cells and specialized phagocytes in the chick embryo retina: A TEM and SEM study

1990 ◽  
Vol 48 (3) ◽  
pp. 330-331
Author(s):  
M.A. Cuadros ◽  
M.J. Martinez-Guerrero ◽  
A. Rios
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Acid Phosphatase ◽  
Chick Embryo ◽  
Basement Membrane ◽  
Sem Images ◽  
Intimate Contact ◽  
Cellular Processes ◽  
Sem Study ◽  
Free Cells

In the chick embryo retina (days 3-4 of incubation), coinciding with an increase in cell death, specialized phagocytes characterized by intense acid phosphatase activity have been described. In these preparations, all free cells in the vitreal humor (vitreal cells) were strongly labeled. Conventional TEM and SEM techniques were used to characterize them and attempt to determine their relationship with retinal phagocytes.Two types of vitreal cells were distinguished. The first are located at some distance from the basement membrane of the neuroepithelium, and are rounded, with numerous vacuoles and thin cytoplasmic prolongations. Images of exo- and or endocytosis were frequent; the cells showed a well-developed Golgi apparatus (Fig. 1) In SEM images, the cells was covered with short cellular processes (Fig. 3). Cells lying parallel to or alongside the basement membrane are elongated. The plasma membrane is frequently in intimate contact with the basement membrane. These cells have generally a large cytoplasmic expansion (Fig. 5).

Targeting Membrane Receptors of Ovarian Cancer Cells for Therapy

2019 ◽  
Vol 19 (6) ◽  
pp. 449-467
Author(s):  
Zhiquan Liang ◽  
Ziwen Lu ◽  
Yafei Zhang ◽  
Dongsheng Shang ◽  
Ruyan Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Receptor Binding ◽  
Cytoreductive Surgery ◽  
Therapeutic Strategies ◽  
Membrane Receptors ◽  
Ovarian Cancer Cells ◽  
Advanced Stage ◽  
Targeted Therapeutics ◽  
Cellular Processes

Ovarian cancer is a leading cause of death worldwide from gynecological malignancies, mainly because there are few early symptoms and the disease is generally diagnosed at an advanced stage. In addition, despite the effectiveness of cytoreductive surgery for ovarian cancer and the high response rates to chemotherapy, survival has improved little over the last 20 years. The management of patients with ovarian cancer also remains similar despite studies showing striking differences and heterogeneity among different subtypes. It is therefore clear that novel targeted therapeutics are urgently needed to improve clinical outcomes for ovarian cancer. To that end, several membrane receptors associated with pivotal cellular processes and often aberrantly overexpressed in ovarian cancer cells have emerged as potential targets for receptor-mediated therapeutic strategies including specific agents and multifunctional delivery systems based on ligand-receptor binding. This review focuses on the profiles and potentials of such strategies proposed for ovarian cancer treatment and imaging.

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

2021 ◽  
pp. 101012
Author(s):  
Anne Sofie Busk Heitmann ◽  
Ali Asghar Hakami Zanjani ◽  
Martin Berg Klenow ◽  
Anna Mularski ◽  
Stine Lauritzen Sønder ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cancer Cells ◽  
Membrane Properties
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