NCS-1 is a regulator of calcium signaling in health and disease

Boeckel, Göran Ramin; Ehrlich, Barbara E.

doi:10.1016/j.bbamcr.2018.05.005

Cited by 53 publications

(43 citation statements)

References 144 publications

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“…Among the 3 targets, we focused on NCS1 because its aberrant expression significantly predicted poor prognosis in patients. The NCS1 protein is a member of the NCS family, which harbors a functional Ca 2+ binding domain and N ‐terminally myristoylated site . Previous studies have reported that NCS1 is a multifunctional protein involved in exocytosis, neurite outgrowth, neuroprotection, axonal regeneration, and nuclear Ca 2+ regulation .…”

Section: Discussionmentioning

confidence: 99%

“…The NCS1 protein is a member of the NCS family, which harbors a functional Ca 2+ binding domain and N ‐terminally myristoylated site . Previous studies have reported that NCS1 is a multifunctional protein involved in exocytosis, neurite outgrowth, neuroprotection, axonal regeneration, and nuclear Ca 2+ regulation . Furthermore, NCS1 interacts with various proteins to control their functions .…”

Section: Discussionmentioning

confidence: 99%

“…45,46 Previous studies have reported that NCS1 is a multifunctional protein involved in exocytosis, neurite outgrowth, neuroprotection, axonal regeneration, and nuclear Ca 2+ regulation. 45,46 Furthermore, NCS1 interacts with various proteins to control their functions. 45,46 For example, NCS1 interacts with D2R and inhibits D2R-mediated signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…45,46 Furthermore, NCS1 interacts with various proteins to control their functions. 45,46 For example, NCS1 interacts with D2R and inhibits D2R-mediated signaling pathways. 47 Interestingly, activation of D2R-mediated signaling suppresses lung cancer aggressiveness.…”

Section: Discussionmentioning

confidence: 99%

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Involvement of dual‐strand of the miR‐144 duplex and their targets in the pathogenesis of lung squamous cell carcinoma

et al. 2018

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The prognosis of patients with advanced‐stage lung squamous cell carcinoma (LUSQ) is poor, and effective treatment protocols are limited. Our continuous analyses of antitumor microRNAs (miRNAs) and their oncogenic targets have revealed novel oncogenic pathways in LUSQ. Analyses of our original miRNA expression signatures indicated that both strands of miR‐144 (miR‐144‐5p, the passenger strand; miR‐144‐3p, the guide strand) showed decreased expression in cancer tissues. Additionally, low expression of miR‐144‐5p significantly predicted a poor prognosis in patients with LUSQ by The Cancer Genome Atlas database analyses (overall survival, P = 0.026; disease‐free survival, P = 0.023). Functional assays revealed that ectopic expression of miR‐144‐5p and miR‐144‐3p significantly blocked the malignant abilities of LUSQ cells, eg, cancer cell proliferation, migration, and invasion. In LUSQ cells, 13 and 15 genes were identified as possible oncogenic targets that might be regulated by miR‐144‐5p and miR‐144‐3p, respectively. Among these targets, we identified 3 genes (SLC44A5, MARCKS, and NCS1) that might be regulated by both strands of miR‐144. Interestingly, high expression of NCS1 predicted a significantly poorer prognosis in patients with LUSQ (overall survival, P = 0.013; disease‐free survival, P = 0.048). By multivariate analysis, NCS1 expression was found to be an independent prognostic factor for patients with LUSQ patients. Overexpression of NCS1 was detected in LUSQ clinical specimens, and its aberrant expression enhanced malignant transformation of LUSQ cells. Our approach, involving identification of antitumor miRNAs and their targets, will contribute to improving our understanding of the molecular pathogenesis of LUSQ.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Involvement of dual‐strand of the miR‐144 duplex and their targets in the pathogenesis of lung squamous cell carcinoma

et al. 2018

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“…NCS1 interacts with a wide range of proteins, including the inositol 1,4,5‐ tris phosphate receptor (InsP3R), dopamine receptor type 2 (D2R), and phosphatidylinositol 4‐OH kinase (PI4K) (35, 36). Through its protein‐protein interactions, NCS1 regulates vital cellular processes such as neurotransmitter release (32), neurite outgrowth and neuronal survival (37, 38), spatial memory formation (31), and the InsP3R signaling pathway (39, 40).…”

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confidence: 99%

Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of breast cancer cells in vitro and in vivo

et al. 2018

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Increased levels of the calcium‐binding protein neuronal calcium sensor 1 (NCS1) predict an unfavorable patient outcome in several aggressive cancers, including breast and liver tumors. Previous studies suggest that NCS1 overexpression facilitates metastatic spread of these cancers. To investigate this hypothesis, we explored the effects of NCS1 overexpression on cell proliferation, survival, and migration patterns in vitro in 2‐ and 3‐dimensional (2/3‐D). Furthermore, we translated our results into an in vivo mouse xenograft model. Cell‐based proliferation assays were used to demonstrate the effects of overexpression of NCS1 on growth rates. In vitro colony formation and wound healing experiments were performed and 3‐D migration dynamics were studied using collagen gels. Nude mice were injected with breast cancer cells to monitor NCS1‐dependent metastasis formation over time. We observed that increased NCS1 levels do not change cellular growth rates, but do significantly increase 2‐ and 3‐D migration dynamics in vitro. Likewise, NCS1‐overexpressing cells have an increased capacity to form distant metastases and demonstrate better survival and less necrosis in vivo. We found that NCS1 preferentially localizes to the leading edge of cells and overexpression increases the motility of cancer cells. Furthermore, this phenotype is correlated with an increased number of metastases in a xenograft model. These results lay the foundation for exploring the relevance of an NCS1‐mediated pathway as a metastatic biomarker and as a target for pharmacologic interventions.—Apasu, J. E., Schuette, D., LaRanger, R., Steinle, J. A., Nguyen, L. D., Grosshans, H. K., Zhang, M., Cai, W. L., Yan, Q., Robert, M. E., Mak, M., Ehrlich, B. E. Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of breast cancer cells in vitro and in vivo. FASEB J. 33, 4802–4813 (2019). http://www.fasebj.org

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NCS‐1 expression is higher in basal breast cancers and regulates calcium influx and cytotoxic responses to doxorubicin

et al. 2019

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Neuronal calcium sensor-1 (NCS-1) is a positive modulator of IP 3 receptors and was recently associated with poorer survival in breast cancers. However, the association between NCS-1 and breast cancer molecular subtypes and the effects of NCS-1 silencing on calcium (Ca 2+ ) signaling in breast cancer cells remain unexplored. Herein, we report for the first time an increased expression of NCS-1 in breast cancers of the basal molecular subtype, a subtype associated with poor prognosis. Using MDA-MB-231 basal breast cancer cells expressing the GCaMP6m Ca 2+ indicator, we showed that NCS-1 silencing did not result in major changes in cytosolic free Ca 2+ increases as a result of endoplasmic reticulum Ca 2+ store mobilization. However, NCS-1 silencing suppressed unstimulated basal Ca 2+ influx. NCS-1 silencing in MDA-MB-231 cells also promoted necrotic cell death induced by the chemotherapeutic drug doxorubicin (1 µM). The effect of NCS-1 silencing on cell death was phenocopied by silencing of ORAI1, a Ca 2+ store-operated Ca 2+ channel that maintains Ca 2+ levels in the endoplasmic reticulum Ca 2+ store and whose expression was significantly positively correlated with NCS-1 in clinical breast cancer samples. This newly identified association between NCS-1 and basal breast cancers, together with the identification of the role of NCS-1 in the regulation of the effects of doxorubicin in MDA-MB-231 breast cancer cells, suggests that NCS-1 and/or pathways regulated by NCS-1 may be important in the treatment of basal breast cancers in women.

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NCS-1 is a regulator of calcium signaling in health and disease

Cited by 53 publications

References 144 publications

Involvement of dual‐strand of the miR‐144 duplex and their targets in the pathogenesis of lung squamous cell carcinoma

Involvement of dual‐strand of the miR‐144 duplex and their targets in the pathogenesis of lung squamous cell carcinoma

Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of breast cancer cells in vitro and in vivo

NCS‐1 expression is higher in basal breast cancers and regulates calcium influx and cytotoxic responses to doxorubicin

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