Journal Article

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

Steinle, Julia A., Grosshans, Henrike K., Brill, Allison L., Ehrlich, Barbara E., Fischer, Tom T.

2020

Overview

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. This study investigates the underlying mechanism by which the calcium (Ca2+)‐binding protein NCS1 promotes increased tumor aggressiveness. We characterize NCS1 as a stress response protein that is up‐regulated by exogenous stressors, including the cytokine tumor necrosis factor α, through a nuclear factor kappa‐light‐chain‐enhancer of activated B cells‐dependent mechanism. Increased NCS1 expression leads to disrupted intracellular Ca2+ signaling and activation of the protein kinase B pathway, leading to increased cell survival and migration.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: AKT protein / Base Sequence / Breast cancer / Ca2+ binding protein / Ca2+ signaling / Calcium (intracellular) / Calcium - metabolism / Calcium buffering / Calcium signalling / Calcium-binding protein / Cell culture / Cell Line, Tumor / Cell migration / Cell Movement - drug effects / Cell Movement - genetics / Cell survival / Cell Survival - drug effects / Cell Survival - genetics / Cellular stress response / Chelating Agents - pharmacology / Cold / CRISPR-Cas Systems - genetics / Cytosol - metabolism / Endoplasmic reticulum / Endoplasmic Reticulum - drug effects / Endoplasmic Reticulum - metabolism / External stimuli / Freq protein / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Homeostasis / Humans / Inflammation / Inositol 1,4,5-trisphosphate receptors / Inositol 1,4,5-Trisphosphate Receptors - metabolism / Intracellular / Intracellular signalling / Kinases / Lymphocytes B / Metastases / Motility / Neoplasms - genetics / Neoplasms - pathology / Neuronal Calcium-Sensor Proteins - genetics / Neuronal Calcium-Sensor Proteins - metabolism / Neuropeptides - genetics / Neuropeptides - metabolism / NF-kappa B - metabolism / NF-κB protein / NFκB / Penicillin / PKB/Akt / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Sensors / Signal Transduction / Stress, Physiological - drug effects / Stress, Physiological - genetics / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-TNF / Tumor necrosis factor-α / tumor progression / Tumors / Up-Regulation - drug effects / Up-Regulation - genetics