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    Differential engagement of ORAI1 and TRPC1 in the induction of vimentin expression by different stimuli.

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    Author
    Stewart, TA; Azimi, I; Marcial, D; Peters, AA; Chalmers, SB; Yapa, KTDS; Thompson, EW; Roberts-Thomson, SJ; Monteith, GR
    Date
    2020-02
    Source Title
    Laboratory Investigation
    Publisher
    Springer Science and Business Media LLC
    University of Melbourne Author/s
    Thompson, Erik
    Affiliation
    Surgery (St Vincent's)
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Stewart, T. A., Azimi, I., Marcial, D., Peters, A. A., Chalmers, S. B., Yapa, K. T. D. S., Thompson, E. W., Roberts-Thomson, S. J. & Monteith, G. R. (2020). Differential engagement of ORAI1 and TRPC1 in the induction of vimentin expression by different stimuli.. Lab Invest, 100 (2), pp.224-233. https://doi.org/10.1038/s41374-019-0280-3.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/253923
    DOI
    10.1038/s41374-019-0280-3
    Open Access URL
    https://eprints.utas.edu.au/31237/1/Paper-lab-investigation-reb-final.pdf
    Abstract
    The Ca2+ signal is essential in both hypoxia- and epidermal growth factor (EGF)-mediated epithelial to mesenchymal transition (EMT) in MDA-MB-468 breast cancer cells. This finding suggests that Ca2+-permeable ion channels participate in the induction of expression of some mesenchymal markers such as vimentin. However, the ion channels involved in vimentin expression induction have not been fully characterized. This work sought to define how differential modulation of the calcium signal effects the induction of vimentin and the Ca2+ influx pathways involved. We identified that the intracellular Ca2+ chelator EGTA-AM, cytochalasin D (a modulator of cytoskeletal dynamics and cell morphology), and the sarco/endoplasmic reticulum ATPase inhibitor thapsigargin are all inducers of vimentin in MDA-MB-468 breast cancer cells. EGTA-AM- and thapsigargin-mediated induction of vimentin expression in MDA-MB-468 cells involves store-operated Ca2+ entry, as evidenced by sensitivity to silencing of the molecular components of this pathway, STIM1 and ORAI1. In stark contrast, cytochalasin D-mediated vimentin induction was insensitive to silencing of ORAI1, despite sensitivity to silencing of its canonical activator the endoplasmic reticulum Ca2+ sensor STIM1. Cytochalasin D-mediated vimentin induction was, however, sensitive to silencing of another reported STIM1 target, TRPC1. Subsequent studies identified that EGTA-AM-induced vimentin expression also partially involved a TRPC1-dependent pathway. These studies define a complex interplay between vimentin expression in this model and the specific Ca2+-permeable ion channels involved. The complexity in the engagement of different Ca2+ influx pathways that regulate vimentin induction are opportunities but also potential challenges in targeting Ca2+ signaling to block EMT in cancer cells. Our findings further highlight the need to identify potential indispensable ion channels that can regulate induction of specific mesenchymal markers via different stimuli.

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