Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells

Azimi, Iman; Monteith, Gregory R.

doi:10.1530/erc-16-0334

Cited by 35 publications

(30 citation statements)

References 53 publications

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“…As a primary tumour develops, the associated hypoxic environment initiates events such as the induction of a more invasive phenotype through EMT (Azimi and Monteith, 2016;Lester et al, 2007) and cell survival via autophagy (Hu et al, 2012). The studies presented here provide evidence for TRPC1 as a critical regulator of processes induced by hypoxia via HIF1α-dependent and -independent mechanisms.…”

Section: Discussionmentioning

confidence: 58%

TRPC1 is a differential regulator of hypoxia-mediated events and Akt signalling in PTEN-deficient breast cancer cells

Azimi

Milevskiy

Kaemmerer

et al. 2017

Journal of Cell Science

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Hypoxia is a feature of the tumour microenvironment that promotes invasiveness, resistance to chemotherapeutics and cell survival. Our studies identify the transient receptor potential canonical-1 (TRPC1) ion channel as a key component of responses to hypoxia in breast cancer cells. This regulation includes control of specific epithelial to mesenchymal transition (EMT) events and hypoxia-mediated activation of signalling pathways such as activation of the EGFR, STAT3 and the autophagy marker LC3B, through hypoxia-inducible factor-1α (HIF1α)-dependent and -independent mechanisms. TRPC1 regulated HIF1α levels in PTEN-deficient MDA-MB-468 and HCC1569 breast cancer cell lines. This regulation arises from effects on the constitutive translation of HIF1α under normoxic conditions via an Akt-dependent pathway. In further support of the role of TRPC1 in EMT, its expression is closely associated with EMT-and metastasisrelated genes in breast tumours, and is enhanced in basal B breast cancer cell lines. TRPC1 expression is also significantly prognostic for basal breast cancers, particularly those classified as lymph node positive. The defined roles of TRPC1 identified here could be therapeutically exploited for the control of oncogenic pathways in breast cancer cells.

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Section: Discussionmentioning

confidence: 58%

TRPC1 is a differential regulator of hypoxia-mediated events and Akt signalling in PTEN-deficient breast cancer cells

Azimi

Milevskiy

Kaemmerer

et al. 2017

Journal of Cell Science

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“…Recently, studies have identified the remodeling of Ca 2+ signaling and/or changes in the expression of components of Ca 2+ transport as a consequence of EMT in cancer cells ( [5,[12][13][14] and reviewed in [15]). The Ca 2+ signal itself is also a key regulator of the induction of EMT by some stimuli.…”

Section: Introductionmentioning

confidence: 99%

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

Stewart

Azimi

Marcial

et al. 2020

Laboratory Investigation

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The Ca 2+ 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 Ca 2+-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 Ca 2+ influx pathways involved. We identified that the intracellular Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+-permeable ion channels involved. The complexity in the engagement of different Ca 2+ influx pathways that regulate vimentin induction are opportunities but also potential challenges in targeting Ca 2+ 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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“…The electrical activity of pancreatic beta-cells relies on multiple types of voltage-and ligand-gated ion channels that are permeable to inorganic ions such as sodium, potassium, chloride and calcium [5], [15], [16]. These channels not only regulate membrane potential, ion homeostasis and electrical signaling [17], but a dis-regulation in their activity has been recently also implicated in tumorogenesis and tumor progression [18], [19], [20], [21].…”

Section: Single Beta-cell Models Of Bursting and Silent Dynamicsmentioning

confidence: 99%

Cooperative maintenance of cellular identity in systems with intercellular communication defects

Stankevich

Koseska

2020

Chaos: An Interdisciplinary Journal of Nonlinear Science

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The cooperative dynamics of cellular populations emerging from the underlying interactions determines cellular functions, and thereby their identity in tissues. Global deviations from this dynamics on the other hand reflects pathological conditions. However, how these conditions are stabilized from dis-regulation on the level of the single entities is still unclear. Here we tackle this question using generic Hodgkin-Huxley type of models that describe physiological bursting dynamics of pancreatic beta-cells, and introduce channel dis-function to mimic pathological silent dynamics. The probability for pathological behavior in beta-cell populations is ∼ 100% when all cell have these defects, despite the negligible size of the silent state basin of attraction for single cells. In stark contrast, in a more realistic scenario for a heterogeneous population, stabilization of the pathological state depends on the size of the sub-population which acquired the defects. However, the probability to exhibit stable pathological dynamics in this case is less than ∼ 10%. These results therefore suggest that the arXiv:1909.02944v2 [q-bio.CB] 23 Sep 2019 physiological bursting dynamics of a population of beta-cells is cooperatively regulated, even under intercellular communication defects induced by dis-functional channels of single-cells.

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Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells

Cited by 35 publications

References 53 publications

TRPC1 is a differential regulator of hypoxia-mediated events and Akt signalling in PTEN-deficient breast cancer cells

TRPC1 is a differential regulator of hypoxia-mediated events and Akt signalling in PTEN-deficient breast cancer cells

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

Cooperative maintenance of cellular identity in systems with intercellular communication defects

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