Neuronal Calcium Sensor 1 is up-regulated in response to stress to promote cell survival and motility in cancer cells.

Abstract

Changes in intracellular calcium (Ca2+ ) signaling can modulate cellular machinery required for cancer progression. Neuronal calcium sensor 1 (NCS1) is a ubiquitously expressed Ca2+ -binding protein that promotes tumor aggressiveness by enhancing cell survival and metastasis. However, the underlying mechanism by which NCS1 contributes to increased tumor aggressiveness has yet to be identified. In this study, we aimed to determine (a) whether NCS1 expression changes in response to external stimuli, (b) the importance of NCS1 for cell survival and migration, and (c) the cellular mechanism(s) through which NSC1 modulates these outcomes. We found that NCS1 abundance increases under conditions of stress, most prominently after stimulation with the pro-inflammatory cytokine tumor necrosis factor α, in a manner dependent on nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). We found that NFκB signaling is activated in human breast cancer tissue, which was accompanied by an increase in NCS1 mRNA expression. Further exploration into the relevance of NCS1 in breast cancer progression showed that knockout of NCS1 (NCS1 KO) caused decreased cell survival and motility, increased baseline intracellular Ca2+ levels, and decreased inositol 1,4,5-trisphosphate-mediated Ca2+ responses. Protein kinase B (Akt) activity was decreased in NCS1 KO cells, which could be rescued by buffering intracellular Ca2+ . Conversely, Akt activity was increased in cells overexpressing NCS1 (NCS1 OE). We therefore conclude that NCS1 acts as cellular stress response protein up-regulated by stress-induced NFκB signaling and that NCS1 influences cell survival and motility through effects on Ca2+ signaling and Akt pathway activation.

• Authors: Henrike K Grosshans, Tom T Fischer, Julia A Steinle, Allison L Brill, Barbara E Ehrlich
• Journal: Molecular oncology (Mol Oncol) Vol. 14 Issue 6 Pg. 1134-1151 (06 2020) ISSN: 1878-0261 [Electronic] United States
• PMID: 32239615 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• Chelating Agents
• Inositol 1,4,5-Trisphosphate Receptors
• NF-kappa B
• Neuronal Calcium-Sensor Proteins
• Neuropeptides
• Tumor Necrosis Factor-alpha
• frequenin calcium sensor proteins
• Proto-Oncogene Proteins c-akt
• Calcium

Topics

• Base Sequence
• CRISPR-Cas Systems (genetics)
• Calcium (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects, genetics)
• Cell Survival (drug effects, genetics)
• Chelating Agents (pharmacology)
• Cytosol (metabolism)
• Endoplasmic Reticulum (drug effects, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Inositol 1,4,5-Trisphosphate Receptors (metabolism)
• NF-kappa B (metabolism)
• Neoplasms (genetics, pathology)
• Neuronal Calcium-Sensor Proteins (genetics, metabolism)
• Neuropeptides (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Stress, Physiological (drug effects, genetics)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation (drug effects, genetics)