Assessment of gene expression of intracellular calcium channels, pumps and exchangers with epidermal growth factor-induced epithelial-mesenchymal transition in a breast cancer cell line
© Davis et al.; licensee BioMed Central Ltd. 2013
Received: 9 May 2013
Accepted: 24 July 2013
Published: 29 July 2013
Epithelial-mesenchymal transition (EMT) is a process implicated in cancer metastasis that involves the conversion of epithelial cells to a more mesenchymal and invasive cell phenotype. In breast cancer cells EMT is associated with altered store-operated calcium influx and changes in calcium signalling mediated by activation of cell surface purinergic receptors. In this study, we investigated whether MDA-MB-468 breast cancer cells induced to undergo EMT exhibit changes in mRNA levels of calcium channels, pumps and exchangers located on intracellular calcium storing organelles, including the Golgi, mitochondria and endoplasmic reticulum (ER).
Epidermal growth factor (EGF) was used to induce EMT in MDA-MB-468 breast cancer cells. Serum-deprived cells were treated with EGF (50 ng/mL) for 12 h and gene expression was assessed using quantitative RT-PCR.
Results and conclusions
These data reveal no significant alterations in mRNA levels of the Golgi calcium pump secretory pathway calcium ATPases (SPCA1 and SPCA2), or the mitochondrial calcium uniporter (MCU) or Na+/Ca2+ exchanger (NCLX). However, EGF-induced EMT was associated with significant alterations in mRNA levels of specific ER calcium channels and pumps, including (sarco)-endoplasmic reticulum calcium ATPases (SERCAs), and inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RYR) calcium channel isoforms. The most prominent change in gene expression between the epithelial and mesenchymal-like states was RYR2, which was enriched 45-fold in EGF-treated MDA-MB-468 cells. These findings indicate that EGF-induced EMT in breast cancer cells may be associated with major alterations in ER calcium homeostasis.
KeywordsBreast cancer calcium EMT IP3R RYR SERCA SPCA MCU NCLX
EMT facilitates cancer cell invasion and metastasis formation, and has also been linked to the acquisition of a stem cell-like phenotype, anchorage-independent growth and chemoresistance in cancer cell lines and clinical samples –. The phenotypic changes associated with EGF-induced EMT are well characterised in the human breast cancer cell line MDA-MB-468, and include changes in cell morphology; increased expression of the transcription factor Twist and the intermediate filament protein vimentin; and reduced E-cadherin expression following chronic EGF treatment –. In addition, EGF-induced EMT in MDA-MB-468 breast cancer cells has been linked to altered plasma membrane calcium influx [6, 7, 9].
Increases in cytosolic calcium may occur via calcium entry through calcium permeable plasma membrane channels, including transient receptor potential (TRP), voltage-gated and store-operated calcium channels, or due to the release of calcium from internal stores –. Calcium signals arising via influx or store-release have distinct spatiotemporal profiles, modes of activation, and cellular responses . These two processes often occur in parallel, for example calcium store release triggering store-operated calcium influx , and calcium influx via specific plasma membrane calcium channels potentially causing calcium release from the ER via calcium-induced calcium release (CICR) . Mitochondrial calcium buffering may also alter the nature of cytosolic calcium responses –. Thus changes in the expression of calcium channels, pumps and exchangers located on intracellular calcium storing organelles may alter the nature of the cytosolic calcium response to a range of stimuli. However, while altered store-operated [6, 9] and non-stimulated  plasmalemmal calcium influx have been linked to the acquisition of a more mesenchymal phenotype in breast cancer cells, changes in calcium channels, pumps and exchangers located on intracellular calcium storing organelles have not been assessed during this process.
A phenotypic conversion and cellular heterogeneity comparable to EMT, which is associated with a remodelling of intracellular calcium homeostasis, is observed in vascular smooth muscle cells . In response to cues from the microenvironment, vascular smooth muscle cells can switch from a contractile to a synthetic (proliferative) phenotype . Vascular smooth muscle cell switching is associated with changes in the expression of ER calcium channels and pumps, including reduced expression of RYR3 and SERCA2a [20, 21]. Vascular smooth muscle cells are therefore one example of how intracellular calcium channels and pumps may be remodelled to meet the cellular requirements of specific phenotypes.
In this study we assessed whether alterations in mRNA levels of Golgi, mitochondrial and ER calcium channels, pumps and exchangers were associated with EGF-induced EMT in MDA-MB-468 breast cancer cells.
Results and discussion
EGF-induced EMT in MDA-MB-468 cells
Golgi: SPCA1 and SPCA2
Mitochondria: MCU and NCLX
Excess mitochondrial calcium accumulation is a trigger for cell death . Downregulation of the MCU in HeLa cervical cancer cells by miR-25 protects cells from calcium-dependent apoptosis, and reduced expression of MCU is a feature of poorly differentiated colonic adenocarcinomas . In contrast, MCU expression appears to be enriched in some breast cancer subtypes associated with a poor clinical prognosis . Although several studies have reported that EMT or expression of EMT-associated transcription factors is associated with apoptosis resistance –, the mechanism underpinning this process has not been characterised. We evaluated changes in gene expression of two key mitochondrial calcium accumulation and release proteins—the MCU [33, 34] and NCLX —in breast cancer cells induced to undergo EMT with EGF. Our results show no significant changes in the expression of the MCU or NCLX with EGF-induced EMT in MDA-MB-468 cells (Figure 2C & D). These findings indicate that if EGF-induced EMT in breast cancer cells is associated with apoptosis-resistance, it is not due to altered gene expression of the MCU or NCLX, at least under these study conditions.
Endoplasmic reticulum: SERCAs, IP3Rs and RYRs
Alterations in the expression of ER calcium channels and pumps occur in cancer cell lines and clinical cancer samples [12, 41]–. For example, expression of SERCA3 is significantly reduced in colon carcinomas and colon cancer cell lines compared to normal colonic epithelia , and SERCA3 expression is elevated with chemically-induced differentiation of colon, gastric and lung cancer cell lines [41, 42]. Therefore, the reduced SERCA3 mRNA levels observed in this study with EGF-induced EMT may reflect a loss of cellular differentiation congruent with the acquisition of a more stem cell-like phenotype. Future studies are needed to assess whether these changes are related to EMT-associated stemness and to assess the various SERCA transcript variants with EGF-induced EMT. Ryanodine receptor expression, using an antibody that detects all ryanodine receptor isoforms, also correlates with breast cancer tumour grade . Furthermore, the induction of RYR2 expression by factors/conditions known to induce EMT in a variety of cell types (including EGF, TGFβ  and hypoxia ), suggests that RYR2 may be a key calcium channel for the mesenchymal cell phenotype. The association between RYR2 and EMT requires further investigation.
We have recently shown that the calcium signal is critically required for EMT induction in breast cancer cells  and that, in addition to regulating the conversion to a more mesenchymal cell phenotype, EMT is associated with a remodelling of non-stimulated, agonist-stimulated and store-operated calcium influx [6, 7]. This study assessed changes in mRNA levels of intracellular calcium channels, pumps and exchangers with EMT. Our results demonstrate that similar to vascular smooth muscle cell phenotypic switching , EMT in breast cancer cells is associated with changes in gene expression of specific ER calcium channels and pumps, the consequence of which may be altered ER calcium storage and signalling. This is in agreement with our previously published data showing altered ER calcium release kinetics with EGF-induced EMT in this cell line . Changes in ER calcium handling may lead to altered responses to phospholipase-C-coupled receptor agonists, and may be important for the invasive properties of mesenchymal-like cancer cells.
Materials and methods
MDA-MB-468 cells were maintained in Dulbecco’s Modified Eagle’s Medium (D6546, Sigma Aldrich) supplemented with penicillin (100 U/mL, Invitrogen), streptomycin (100 μg/mL, Invitrogen), fetal bovine serum (10%, Sigma Aldrich) and L-glutamine (4 mM, Invitrogen) . To induce EMT, MDA-MB-468 cells were serum-starved (0.5% fetal bovine serum) for 24 h and stimulated with EGF (50 ng/mL, Sigma Aldrich) for 12 h (gene expression) or 24 h (calcium assays) –. These time points were chosen because changes in mRNA levels are expected to precede changes in functional responses. MDA-MB-468 cells were maintained in a humidified incubator at 37°C with 5% CO2 and routinely tested negative for mycoplasma infection (MycoAlert, Lonza). Short tandem repeat (STR) profiling of the MDA-MB-468 cell line was performed by the Queensland Institute of Medical Research using the StemElite ID Profiling Kit (Promega).
RNA isolation and real-time RT-PCR
Total RNA was isolated and purified using the RNeasy Plus Mini Kit (Qiagen). RNA (1000 ng) was reverse transcribed using the Omniscript RT Kit (Qiagen) and cDNA amplified using TaqMan Universal PCR Master Mix or TaqMan FAST Universal PCR Master Mix with a StepOnePlus Real Time PCR System (Applied Biosystems). The following Gene Expression Assays (Applied Biosystems) were used in this study: IP3R1 (Hs00181881_m1), IP3R2 (Hs00181916_m1), IP3R3 (Hs01573555_m1), MCU (Hs00293548_m1), NCLX (Hs00227951_m1), RYR1 (Hs00166991_m1), RYR2 (Hs00892840_m1), RYR3 (Hs00168821_m1), SERCA1 (Hs01092295_m1), SERCA2 (Hs00544877_m1), SERCA3 (Hs00193090_m1), SPCA1 (Hs00205122_m1), SPCA2 (Hs00208296_m1), Twist (Hs00361186_m1) and Vimentin (Hs00185584_m1). Relative quantification was calculated with reference to 18S rRNA and analysed using the comparative CT method . Targets registering above the limit of detection or having CT values greater than 35 were assigned a value of 35.
FLIPR calcium assays
Measurement of [Ca2+]CYT responses to caffeine was performed using a fluorometric imaging plate reader (FLIPRTETRA, Molecular Devices) as previously described . Briefly, cells were loaded with Fluo-4 AM (2 μM) in a solution containing PBX Signal Enhancer (5%; PBX No Wash Ca2+ Assay Kit, BD Biosciences) and probenecid (500 μM) in physiological salt solution (KCl 5.9 mM, MgCl2 1.4 mM, HEPES 10 mM, NaH2PO4 1.2 mM, NaHCO3 5 mM, NaCl 140 mM, glucose 11.5 mM and CaCl2 1.8 mM) [6, 50]. Calcium measurements were performed with 470/95 and 515/75 nm excitation and emission filters. Fluorescent values were normalised to the point immediately following agonist addition and are expressed as response over baseline.
Statistical analysis was performed using GraphPad Prism (v6.0 for Windows). Statistical tests used in this study are outlined in each figure legend.
Cytosolic calcium concentration
Calcium-induced calcium release
Epidermal growth factor
Fluorometric imaging plate reader
Inositol 1,4,5-trisphosphate receptor
Mitochondrial calcium uniporter
Plasma membrane calcium ATPase
Reverse transcription polymerase chain reaction
(sarco)-Endoplasmic reticulum calcium ATPase
Secretory pathway calcium ATPase
Transient receptor potential.
This research was partially supported by the National Health and Medical Research Council (NHMRC) [project grants 569645, 1022263 and 1027527] and the National Breast Cancer Foundation (EMPathy National Collaborative Research Program). FD was funded by an NHMRC Biomedical Postgraduate Scholarship . St. Vincent’s Institute received support from the Victorian State Government’s Operational Infrastructure Support Program.
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