Abstract
Breast cancer remains a research priority due to its invasive phenotype. Although the role of ion channels in cancer is now well established, the role of inositol (1,4,5)-trisphosphate (IP3) receptors (IP3Rs) remains enigmatic. If the three IP3Rs subtypes expression have been identified in various cancers, little is known about their physiological role. Here, we investigated the involvement of IP3R type 3 (IP3R3) in the migration processes of three human breast cancer cell lines showing different migration velocities: the low-migrating MCF-7 and the highly migrating and invasive MDA-MB-231 and MDA-MB-435S cell lines. We show that a higher IP3R3 expression level, but not IP3R1 nor IP3R2, is correlated to a stronger cell line migration capacity and a sustained calcium signal. Interestingly, silencing of IP3R3 highlights an oscillating calcium signaling profile and leads to a significant decrease of cell migration capacities of the three breast cancer cell lines. Conversely, stable overexpression of IP3R3 in MCF-7 cells significantly increases their migration capacities. This effect is completely reversed by IP3R3 silencing. In conclusion, we demonstrate that IP3R3 expression level increases the migration capacity of human breast cancer cells by changing the calcium signature.
Highlights
Most frequently occurring cancer in women, breast cancer presents the highest death rate
IP3R type 3 (IP3R3) expression level is correlated to migration capacity of breast cancer cell lines
This correlation between the cell migration potential and the IP3R3 expression is specific to IP3R3 subtype, since it is not observed with the others IP3R1 and IP3R2 subtypes (Figure 2)
Summary
Most frequently occurring cancer in women, breast cancer presents the highest death rate. Cancer mortality is not correlated to tumor growth (due to proliferation mechanisms) but, in 90% of cases, to formation of metastasis [1] by migrating and invading cells. One of the mechanisms behind this invasion and metastasis process in breast cancer is the epithelial– mesenchymal transition (EMT) that allows epithelial cancer cells to dedifferentiate and undergo the rear-tofront polarization and to acquire high migratory capacity, invasiveness, enhanced resistance to apoptosis, and stem cell properties [2, 3]. Ca2+ increases can occur in the form of waves, spikes or oscillations with various impact on cell migration progression [7]. Several plasma membrane channels that increase Ca2+ into the cytosol, such as the transient receptor potential (TRP) channels [8] and Orai/STIM channels [9, 10] have been described in cancer cell migration, but implication of inositol-(1,4,5)-trisphosphate (IP3) receptors (IP3Rs) [11]
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