Blockage of intermediate-conductance-Ca2+-activated K+ channels inhibits progression of human endometrial cancer

Wang, Z H; Shen, Bing; Yao, Hailan; Jia, Yichang; Ren, Jin; Yan, Feng; Wang, Y Z

doi:10.1038/sj.onc.1210308

Cited by 96 publications

(86 citation statements)

References 28 publications

(31 reference statements)

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“…Our observation that both growth factor‐evoked and spontaneous Ca 2+ transients in PyMT breast tumour cells do require SK4 activity is consistent with the TRAM‐34 sensitivity of the cell cycle and abundance of c‐fos and c‐jun (Lai et al ., 2011; Ouadid‐Ahidouch et al ., 2004; Wang et al ., 2007b). Previous work identified hERG1, Kv1.1, BK and several other K + channels including SK4 to cause membrane hyperpolarization, which modifies the passive Ca 2+ entry in nonexcitable cancer cells (Ouadid‐Ahidouch and Ahidouch, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…A hyperpolarization of the breast tumour cell membrane reportedly resulted in elevated [Ca 2+ ] i (Wang et al ., 1998), which in turn may activate K Ca to control spatiotemporal Ca 2+ dynamics. Accordingly, the SK4 inhibitors TRAM‐34 and clotrimazole reduced Ca 2+ entry and cell cycle progression as shown for colon and endometrium cancer cells (Lai et al ., 2011; Wang et al ., 2007b). In the metastatic breast cancer cell line MDA‐MB‐231, suppression of SK4 channels with TRAM‐34 or siRNA inhibits both cell proliferation and migration and induces apoptosis (Zhang et al ., 2016).…”

Section: Introductionmentioning

confidence: 99%

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SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

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Oncogenic signalling via Ca2+‐activated K+ channels of intermediate conductance (SK4, also known as KCa3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumorigenesis is unclear. Herein, we generated SK4‐negative tumours by crossing SK4‐deficient (SK4 KO) mice to the polyoma middle T‐antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promoter MMTV. Survival parameters and tumour progression were studied in cancer‐prone SK4 KO in comparison with wild‐type (WT) mice and in a syngeneic orthotopic mouse model following transplantation of SK4‐negative or WT tumour cells. SK4 activity was modulated by genetic or pharmacological means using the SK4 inhibitor TRAM‐34 in order to establish the role of breast tumour SK4 for cell growth, electrophysiological signalling, and [Ca2+]i oscillations. Ablation of SK4 and TRAM‐34 treatment reduced the SK4‐generated current fraction, growth factor‐dependent Ca2+ entry, cell cycle progression and the proliferation rate of MMTV‐PyMT tumour cells. In vivo, PyMT oncogene‐driven tumorigenesis was only marginally affected by the global lack of SK4, whereas tumour progression was significantly delayed after orthotopic implantation of MMTV‐PyMT SK4 KO breast tumour cells. However, overall survival and progression‐free survival time in the MMTV‐cNeu mouse model were significantly extended in the absence of SK4. Collectively, our data from murine breast cancer models indicate that SK4 activity is crucial for cell cycle control. Thus, the modulation of this channel should be further investigated towards a potential improvement of existing antitumour strategies in human breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

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“…The importance of K Ca 3.1 in renal fibroblast mitogenesis may be explained by its ability to enhance the driving force for Ca 2ϩ influx via membrane hyperpolarization and thus sustain a high intracellular Ca 2ϩ concentration needed for gene transcription, as has been reported in VSMC, T lymphocytes and cancer cells (17,20,24,27,28,35,36). Membrane hyperpolarization mediated by potassium channels is known to promote Ca 2ϩ inflow during G 1 of the cell cycle allowing transition through the G 1 /S checkpoint (37).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the results from both studies, using either a genetic or a pharmacological approach, corroborate the proposed concept that K Ca 3.1 channels play an important role in the pathogenesis of renal fibrosis. Of note, in animal models of acute vascular injury (17,19), atherosclerosis (26), angiogenesis (15), and endometrial cancer (27), administration of selective K Ca 3.1 blockers has been shown to also prevent excessive cell proliferation in vivo and ameliorate the course of disease. Importantly, long-term treatment with TRAM-34 at therapeutic concentrations caused no discernible toxicity and did not compromise immune responses in mice and rats (17,26), which is in line with observations of the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, we and others have recently demonstrated in models of experimental angiogenesis (15), post-interventional arterial restenosis (17,19), atherosclerosis (26), and endometrial cancer (27), that selective pharmacological inhibition or knockdown of K Ca 3.1 suppresses mitogen-driven cell proliferation and ameliorates disease progression. Thus, K Ca 3.1 could have a pivotal role in disease states characterized by excessive cell proliferation and may emerge as a promising pharmacotherapeutic target for antiproliferative treatment.…”

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confidence: 99%

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Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels

Grgic

Kiss

Kaistha

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

143

137

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Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca 2+ -activated K + channel (K Ca 3.1) has been proposed to promote mitogenesis in several cell types and contribute to disease states characterized by excessive proliferation. Here, we hypothesized that K Ca 3.1 activity is pivotal for renal fibroblast proliferation and that deficiency or pharmacological blockade of K Ca 3.1 suppresses development of renal fibrosis. We found that mitogenic stimulation up-regulated K Ca 3.1 in murine renal fibroblasts via a MEK-dependent mechanism and that selective blockade of K Ca 3.1 functions potently inhibited fibroblast proliferation by G 0 /G 1 arrest. Renal fibrosis induced by unilateral ureteral obstruction (UUO) in mice was paralleled by a robust up-regulation of K Ca 3.1 in affected kidneys. Mice lacking K Ca 3.1 (K Ca 3.1 −/− ) showed a significant reduction in fibrotic marker expression, chronic tubulointerstitial damage, collagen deposition and αSMA + cells in kidneys after UUO, whereas functional renal parenchyma was better preserved. Pharmacological treatment with the selective K Ca 3.1 blocker TRAM-34 similarly attenuated progression of UUO-induced renal fibrosis in wild-type mice and rats. In conclusion, our data demonstrate that K Ca 3.1 is involved in renal fibroblast proliferation and fibrogenesis and suggest that K Ca 3.1 may represent a therapeutic target for the treatment of fibrotic kidney disease.

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Roles of Ion Transport in Control of Cell Motility

Stock

Ludwig

Hanley

et al. 2013

Comprehensive Physiology

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Cell motility is an essential feature of life. It is essential for reproduction, propagation, embryonic development, and healing processes such as wound closure and a successful immune defense. If out of control, cell motility can become life-threatening as, for example, in metastasis or autoimmune diseases. Regardless of whether ciliary/flagellar or amoeboid movement, controlled motility always requires a concerted action of ion channels and transporters, cytoskeletal elements, and signaling cascades. Ion transport across the plasma membrane contributes to cell motility by affecting the membrane potential and voltage-sensitive ion channels, by inducing local volume changes with the help of aquaporins and by modulating cytosolic Ca(2+) and H(+) concentrations. Voltage-sensitive ion channels serve as voltage detectors in electric fields thus enabling galvanotaxis; local swelling facilitates the outgrowth of protrusions at the leading edge while local shrinkage accompanies the retraction of the cell rear; the cytosolic Ca(2+) concentration exerts its main effect on cytoskeletal dynamics via motor proteins such as myosin or dynein; and both, the intracellular and the extracellular H(+) concentration modulate cell migration and adhesion by tuning the activity of enzymes and signaling molecules in the cytosol as well as the activation state of adhesion molecules at the cell surface. In addition to the actual process of ion transport, both, channels and transporters contribute to cell migration by being part of focal adhesion complexes and/or physically interacting with components of the cytoskeleton. The present article provides an overview of how the numerous ion-transport mechanisms contribute to the various modes of cell motility.

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Blockage of intermediate-conductance-Ca2+-activated K+ channels inhibits progression of human endometrial cancer

Cited by 96 publications

References 28 publications

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels

Roles of Ion Transport in Control of Cell Motility

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Blockage of intermediate-conductance-Ca2+-activated K+ channels inhibits progression of human endometrial cancer

Cited by 96 publications

References 28 publications

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

Renal fibrosis is attenuated by targeted disruption of K Ca 3.1 potassium channels

Roles of Ion Transport in Control of Cell Motility

Contact Info

Product

Resources

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SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels