STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization

Didiášová, Miroslava; Zakrzewicz, Dariusz; Magdolen, Viktor; Nagaraj, Chandran; Bálint, Zoltán; Rohde, Manfred; Preissner, Klaus T.; Wygrecka, Małgorzata

doi:10.1074/jbc.m114.598425

Cited by 38 publications

(48 citation statements)

References 59 publications

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“…Our data also confirm previously studies identifying LPS exposure among the stimuli that upregulate cell surface alpha-enolase in monocytoid cells and breast cancer cells 7, 10 , in accordance to the presence of TLR4 receptors in both cell types 9, 38, 39 . The results are in agreement with the notion that stimuli promoting tumour progression, as demonstrated for TGF-α, TNF-α and CCL2 in MDA-MB-231 cells 10 , trigger surface alpha-enolase expression.…”

Section: Discussionsupporting

confidence: 92%

Pro-invasive stimuli and the interacting protein Hsp70 favour the route of alpha-enolase to the cell surface

Perconti

Maranto

Romancino

et al. 2017

Sci Rep

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Cell surface expression of alpha-enolase, a glycolytic enzyme displaying moonlighting activities, has been shown to contribute to the motility and invasiveness of cancer cells through the protein nonenzymatic function of binding plasminogen and enhancing plasmin formation. Although a few recent records indicate the involvement of protein partners in the localization of alpha-enolase to the plasma membrane, the cellular mechanisms underlying surface exposure remain largely elusive. Searching for novel interactors and signalling pathways, we used low-metastatic breast cancer cells, a doxorubicinresistant counterpart and a non-tumourigenic mammary epithelial cell line. Here, we demonstrate by a combination of experimental approaches that epidermal growth factor (EGF) exposure, like lipopolysaccharide (LPS) exposure, promotes the surface expression of alpha-enolase. We also establish Heat shock protein 70 (Hsp70), a multifunctional chaperone distributed in intracellular, plasma membrane and extracellular compartments, as a novel alpha-enolase interactor and demonstrate a functional involvement of Hsp70 in the surface localization of alpha-enolase. Our results contribute to shedding light on the control of surface expression of alpha-enolase in non-tumourigenic and cancer cells and suggest novel targets to counteract the metastatic potential of tumours.An increasing number of proteins are being identified as multifunctional 1 . Most of these are enzymes, which in addition to their catalytic function are involved in fully unrelated processes, such as the glycolytic enzyme alpha-enolase, which was one of the first moonlighting proteins to be identified 2 . Multiple subcellular localizations characterize alpha-enolase, which functions as a plasminogen receptor when localized on the cell surface, and available data have demonstrated its interaction with plasminogen in prokaryotic and eukaryotic cells 3 . Mammalian tumour cells use the activation of plasminogen in plasmin to invade tissue and form metastases 4 . Recently, researchers have linked both pericellular plasminogen activation and cell surface alpha-enolase to migration and invasion in lung and pancreatic cancer, and these studies have proposed targeting cancer cells with specific anti-alpha-enolase antibodies as a promising approach to suppress tumour metastasis 5,6 . Due to the large interest in novel therapeutic strategies to counteract cancer spreading, stimuli and signalling pathways that can cooperate to induce the surface localization of alpha-enolase are attractive objects of study.Increased expression of surface alpha-enolase following LPS exposure was originally reported for the U937 macrophage cell line and human blood monocytes 7 . LPS, a component of the outer membrane of Gram-negative bacteria, exerts its biological effects by binding to Toll-like receptor 4 (TLR4), a recognition receptor of the innate immune system. Some evidence shows that functional TLR4 receptors are expressed on a variety of tumours, including breast cancer, where the silencing...

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Section: Discussionsupporting

confidence: 92%

Pro-invasive stimuli and the interacting protein Hsp70 favour the route of alpha-enolase to the cell surface

Perconti

Maranto

Romancino

et al. 2017

Sci Rep

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“…This Ca 2+ -, Munc13-4–, and Rab11-dependent pathway generated secretion-competent MVBs for basal and Ca 2+ -stimulated CD63 + exosome release. We propose that the increased expression of Munc13-4 in cancer cells after epithelial-to-mesenchymal transition combined with increased Ca 2+ uptake ( Yang et al, 2009 ; Feng et al, 2010 ; Prevarskaya et al, 2011 ; Sun et al, 2014 ; Didiasova et al, 2015 ) drives enhanced exosome release by highly aggressive cancer cells, and that Munc13-4 is a potential target for therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

A Ca2+-stimulated exosome release pathway in cancer cells is regulated by Munc13-4

Messenger

Woo

Sun

et al. 2018

Journal of Cell Biology

172

171

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“…These effects were mediated in part through changes in focal adhesion molecule turn over [41]. In MDA-MB-231 breast cancer cells, ORAI1 is also important in the translocation and release of enolase-1 that regulates the invasion process [52]. This adds a further dimension to how ORAI1 may influence breast cancer metastasis.…”

Section: Orai Channels and Cancer Cell Proliferationmentioning

confidence: 99%

ORAI channels and cancer

Chalmers

Monteith

2018

Cell Calcium

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Cancer is a major cause of death. The diversity of cancer types and the propensity of cancers to acquire resistance to therapies, including new molecularly targeted and immune-based therapies, drives the search for new ways to understand cancer progression. The remodelling of calcium (Ca) signalling and the role of the Ca signal in controlling key events in cancer cells such as proliferation, invasion and the acquisition of resistance to cell death pathways is well established. Most of the work defining such changes has focused on Ca permeable Transient Receptor Potential (TRP) Channels and some voltage gated Ca channels. However, the identification of ORAI channels, a little more than a decade ago, has added a new dimension to how a Ca influx pathway can be remodelled in some cancers and also how calcium signalling could contribute to tumour progression. ORAI Ca channels are now an exemplar for how changes in the expression of specific isoforms of a Ca channel component can occur in cancer, and how such changes can vary between cancer types (e.g. breast cancer versus prostate cancer), and even subtypes (e.g. oestrogen receptor positive versus oestrogen receptor negative breast cancers). ORAI channels and store operated Ca entry are also highlighting the diverse roles of Ca influx pathways in events such as the growth and metastasis of cancers, the development of therapeutic resistance and the contribution of tumour microenvironmental factors in cancer progression. In this review we will highlight some of the studies that have provided evidence for the need to deepen our understanding of ORAI Ca channels in cancer. Many of these studies have also suggested new ways on how we can exploit the role of ORAI channels in cancer relevant processes to develop or inform new therapeutic strategies.

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STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization

Cited by 38 publications

References 59 publications

Pro-invasive stimuli and the interacting protein Hsp70 favour the route of alpha-enolase to the cell surface

Pro-invasive stimuli and the interacting protein Hsp70 favour the route of alpha-enolase to the cell surface

A Ca2+-stimulated exosome release pathway in cancer cells is regulated by Munc13-4

ORAI channels and cancer

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