Abstract
The dysregulation of store-operated Ca2+ entry (SOCE) promotes cancer progression by changing Ca2+ levels in the cytosol or endoplasmic reticulum. Stromal interaction molecule 1 (STIM1), a component of SOCE, is upregulated in several types of cancer and responsible for cancer cell migration, invasion, and metastasis. To explore the impact of STIM1-mediated SOCE on the turnover of focal adhesion (FA) and cell migration, we overexpressed the wild-type and constitutively active or dominant negative variants of STIM1 in an osteosarcoma cell line. In this study, we hypothesized that STIM1-mediated Ca2+ elevation may increase cell migration. We found that constitutively active STIM1 dramatically increased the Ca2+ influx, calpain activity, and turnover of FA proteins, such as the focal adhesion kinase (FAK), paxillin, and vinculin, which impede the cell migration ability. In contrast, dominant negative STIM1 decreased the turnover of FA proteins as its wild-type variant compared to the cells without STIM1 overexpression while promoting cell migration. These unexpected results suggest that cancer cells need an appropriate amount of Ca2+ to control the assembly and disassembly of focal adhesions by regulating calpain activity. On the other hand, overloaded Ca2+ results in excessive calpain activity, which is not beneficial for cancer metastasis.
Highlights
Calcium (Ca2+) signaling is involved in various cellular events ranging from cell life to cell death, including cell proliferation, differentiation, migration, apoptosis, and necrosis [1]
We overexpressed different fluorescent protein-tagged Stromal interaction molecule 1 (STIM1) variants, including SIMT1-wildtype (WT)-enhanced green fluorescent protein (EGFP), STIM1-D76A-EGFP, and STIM1-D76A-∆ezrin–radixin– moesin (ERM)-enhanced yellow fluorescent protein (EYFP) in U2OS osteosarcoma cell lines to further investigate whether cancer cell migration can be affected by manipulating store-operated Ca2+ entry (SOCE) levels through STIM1 activity
We demonstrated how different SOCE levels induced by three different STIM1 variants affect focal adhesion (FA) dynamics and cell migration
Summary
Calcium (Ca2+) signaling is involved in various cellular events ranging from cell life to cell death, including cell proliferation, differentiation, migration, apoptosis, and necrosis [1]. Some studies have identified STIM1 as a tumor suppressor because its overexpression in some specific types of cancers leads to cancer cell death or has no effects on the cells [13,14]. These findings suggest that STIM1 may have multiple regulatory mechanisms in different cancer cells [15,16], further implying the importance of Ca2+ homeostasis controlled by STIM1mediated SOCE in cancer
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