Inhibition of store-operated Ca2+ entry counteracts the apoptosis of nasopharyngeal carcinoma cells induced by sodium butyrate

Huang, Wei; Ren, Chao; Huang, Guoling; Liu, Jie; Liu, Weidong; Wang, Lei; Zhu, Bin; Feng, Xiangling; Song, Jia; Li, Jinlong; Xia, Xiaomeng; Jia, Wei Hua; Chen, Jiawen; Chen, Yuxiang; Jiang, Xingjun

doi:10.3892/ol.2016.5469

Cited by 21 publications

(10 citation statements)

References 36 publications

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“…Our data reveal that calcineurin activity is reduced in melanoma cells, and this can lead to loss-of-function (growth, migration) as well as gain-of-function (attachment to matrix) that may perturb in vivo disease progression. Substantial Ca 2+ flux gain-of-function hindering survival and progression of cancers cells has also been shown by studies in which sodium butyrate, a histone deacetylase inhibitor, induced apoptosis in nasopharyngeal carcinoma cells by enhancing SOCE [ 25 ]. This notion of optimal levels of Ca 2+ flux being important was supported by a study in which overexpression of Orai1 in A459 lung cancer cells inhibited EGF-mediated cell proliferation [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Selenoprotein K deficiency inhibits melanoma by reducing calcium flux required for tumor growth and metastasis

et al. 2018

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Interest has emerged in the therapeutic potential of inhibiting store operated calcium (Ca2+) entry (SOCE) for melanoma and other cancers because malignant cells exhibit a strong dependence on Ca2+ flux for disease progression. We investigated the effects of deleting Selenoprotein K (SELENOK) in melanoma since previous work in immune cells showed SELENOK was required for efficient Ca2+ flux through the endoplasmic reticulum Ca2+ channel protein, inositol 1,4,5-trisphosphate receptor (IP3R), which is due to the role SELENOK plays in palmitoylating and stabilizing the expression of IP3R. CRISPR/Cas9 was used to generate SELENOK-deficiency in human melanoma cells and this led to reduced Ca2+ flux and impaired IP3R function, which inhibited cell proliferation, invasion, and migration. Ca2+-dependent signaling through calcineurin was inhibited with SELENOK-deficiency, and gene array analyses together with evaluation of transcript and protein levels showed altered transcriptional programs that ultimately disrupted stemness and pro-growth properties. In vivo investigations were conducted using the Grm1-Tg transgenic mouse strain that develops spontaneous metastatic melanoma, which was crossed with SELENOK−/− mice to generate the following littermates: Grm1-Tg/SELENOK−/−, Grm1-Tg/SELENOK−/+, Grm1-Tg/SELENOK+/+. SELENOK-deficiency in Grm1-Tg/SELENOK−/− male and female mice inhibited primary tumor growth on tails and ears and reduced metastasis to draining lymph nodes down to levels equivalent to non-tumor control mice. Cancer stem cell pools were also decreased in Grm1-Tg/SELENOK−/− mice compared to littermates. These results suggest that melanoma requires SELENOK expression for IP3R dependent maintenance of stemness, tumor growth and metastasic potential, thus revealing a new potential therapeutic target for treating melanoma and possibly other cancers.

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Section: Discussionmentioning

confidence: 99%

Selenoprotein K deficiency inhibits melanoma by reducing calcium flux required for tumor growth and metastasis

et al. 2018

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“…Up-regulation of STIM1/Orai1 has been reported to trigger apoptosis in several cells. For example, down-regulation of STIM1/Orai1 counteracts the apoptosis of nasopharyngeal carcinoma cells induced by NaBu [ 22 ]. Similarly, down-regulated SOCE by SiRNA targeting STIM1 significantly inhibited soft substrate-induced epithelial cell apoptosis [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Suppression of Stim1 reduced intracellular calcium concentration and attenuated hypoxia/reoxygenation induced apoptosis in H9C2 cells

et al. 2017

Bioscience Reports

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Objective: Previous studies have demonstrated Stromal interaction molecule 1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) contributes to intracellular Ca2+ accumulation. The present study aimed to investigate the expression of STIM1 and its downstream molecules Orai1/TRPC1 in the context of myocardial ischemia/reperfusion injury (MIRI) and the effect of STIM1 inhibition on Ca2+ accumulation and apoptosis in H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R).Methods: Expression of STIM1/Orai1/TRPC1 was determined by RT-PCR and Western blot in mice subjected to MIRI and H9C2 cardiomyocytes subjected to H/R. To knock-down STIM1, H9C2 cardiomyocytes was transfected with Stealth SiRNA. Apoptosis was analyzed by both flow cytometry and TUNEL assay. Cell viability was measured by MTT assay. Intracellular Ca2+ concentration was detected by laser scanning confocal microscopy using Fluo-3/AM probe. Furthermore, the opening of mitochondrial permeability transition pore (mPTP) was assessed by coloading with calcein AM and CoCl2, while ROS generation was evaluated using the dye DCFH-DA in H9C2 cardiomyocytes.Results: Expression of STIM1/Orai1/TRPC1 significantly increased in transcript and translation level after MIRI in vivo and H/R in vitro. In H9C2 cardiomyocytes subjected to H/R, intracellular Ca2+ accumulation significantly increased compared with control group, along with enhanced mPTP opening and elevated ROS generation. However, suppression of STIM1 by SiRNA significantly decreased apoptosis and intracellular Ca2+ accumulation induced by H/R in H9C2 cardiomyocytes, accompanied by attenuated mPTP opening and decreased ROS generation. In addition, suppression of STIM1 increased the Bcl-2/Bax ratio, decreased Orai1/TRPC1, and cleaved caspase-3 expression.Conclusion: Suppression of STIM1 reduced intracellular calcium level and attenuated hypoxia/reoxygenation induced apoptosis in H9C2 cardiomyocytes. Our findings provide a new perspective in understanding STIM1-mediated calcium overload in the setting of MIRI.

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“…This down regulation of SOCE in prostate cancer cells may then bestow apoptotic resistance to agents such as tumour necrosis factor α and cisplatin[57]. Indeed, a number of subsequent studies from a diverse set of researchers have reported the ability of ORAI1 silencing and/or suppression of SOCE (via pharmacology agents or STIM silencing) to reduce induced cell death in a variety of cell types[58][59][60]. However, increasing SOCE should not always be seen as a way to induce cell death.…”

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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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Inhibition of store-operated Ca2+ entry counteracts the apoptosis of nasopharyngeal carcinoma cells induced by sodium butyrate

Cited by 21 publications

References 36 publications

Selenoprotein K deficiency inhibits melanoma by reducing calcium flux required for tumor growth and metastasis

Selenoprotein K deficiency inhibits melanoma by reducing calcium flux required for tumor growth and metastasis

Suppression of Stim1 reduced intracellular calcium concentration and attenuated hypoxia/reoxygenation induced apoptosis in H9C2 cells

ORAI channels and cancer

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