Extracellular nucleotides stimulate proliferation in MCF-7 breast cancer cells via P2-purinoceptors

Dixon, C. Jane; Wb, Bowler; Fleetwood, P; Ginty, AF; Gallagher, J.A.; Carron, J.A.

doi:10.1038/bjc.1997.6

Cited by 79 publications

(51 citation statements)

References 35 publications

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“…In contrast, P2Y receptor activation has been shown to inhibit DNA synthesis in cultured cardiac fibroblasts and myocytes (56,57). However, there is evidence suggesting that ATP stimulated cell proliferation via the P2 receptors (3,11,15). The reason for the different responses to extracellular ATP among the cell types is not clear.…”

Section: Discussionmentioning

confidence: 73%

Role of ATP in DNA synthesis of renal proximal tubule cells: involvement of calcium, MAPKs, and CDKs

Lee¹,

Han²

2006

American Journal of Physiology-Renal Physiology

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though ATP has been shown to act as a modulator in various kidney functions, its effect on renal proximal tubule cell (PTC) proliferation has not been elucidated. This study investigated the effect of ATP on cell proliferation and the effect of its related signal pathways on primary cultured PTCs. Treatment with Ͼ10 Ϫ5 M ATP for 1 h stimulated incorporation of thymidine and bromodeoxyuridine. ATP (10 Ϫ4 M)-induced stimulation of thymidine incorporation was blocked by suramin (a P2X and P2Y receptor antagonist), reactive blue 2 (a P2Y receptor antagonist), MRS-2159 (a P2X1 receptor antagonist), and MRS-2179 (a P2Y1 receptor antagonist). ATP increased intracellular Ca 2ϩ concentration, which was blocked by suramin, methoxyverapamil, and EGTA. ATP-induced stimulation of cell proliferation was also blocked by EGTA (an extracellular Ca 2ϩ chelator), methoxyverapamil (a Ca 2ϩ antagonist), and nifedipine (an L-type Ca 2ϩ channel blocker), suggesting a role for Ca 2ϩ influx. ATP-induced phosphorylation of p38 and p44/42 MAPKs was blocked by nifedipine. ATP increased expression levels of cyclindependent kinase (CDK)-2, CDK-4, and cyclin E, which were blocked by suramin, reactive blue 2, MRS-2179, MRS-2159, and nifedipine. However, ATP decreased expression levels of p21 WAF1/Cip1 and p27 kip1 . ATP-induced stimulation of thymidine incorporation and increase of CDK-2 and CDK-4 expression were blocked by SB-203580 (a p38 MAPK inhibitor) and PD-98059 (an MEK inhibitor), but not by SP-600125 (a JNK inhibitor). In conclusion, ATP stimulates proliferation by increasing intracellular Ca 2ϩ concentration and activating p38, p44/42 MAPKs, and CDKs in PTCs. cell proliferation; calcium influx RENAL EPITHELIAL CELLS RELEASE a significant number of nucleotides into the nephron tubules. The released ATP plays an important role in a variety of cells, including epithelial cells, and mediates or modulates a range of physiological process (17,18,47). It has been reported that ATP significantly increases the [ 3 H]thymidine uptake of growth-arrested mesangial cells via P2-purinergic receptors (45). P2X receptors form ligand-gated, nonselective cation channels, whereas the P2Y receptor is a G protein-coupled membrane protein (25). It has been reported that proximal tubule cells (PTCs) express P2X and P2Y receptors, which suggests that these receptors might play a role in DNA synthesis and proliferation in renal PTCs (13, 16). Recently, Ca 2ϩ has been shown to be an essential regulator of the cell cycle, and the duration of the Ca 2ϩ response controls a wide range of cell functions, including proliferation (15). Indeed, the proliferation of PTCs is accompanied by modifications in Ca 2ϩ homeostasis (2,12,20).Therefore, an ATP-induced elevation of intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) might be of particular importance in regulation of cell proliferation (4). However, there is little information on the regulatory mechanisms of cell proliferation by ATP in renal PTCs.In addition to [Ca 2ϩ ] i , mitogen-activated protein kinase (MAP...

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Section: Discussionmentioning

confidence: 73%

Role of ATP in DNA synthesis of renal proximal tubule cells: involvement of calcium, MAPKs, and CDKs

Lee¹,

Han²

2006

American Journal of Physiology-Renal Physiology

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“…The anti-cancer activity of ATP has been reported by many groups, which have reported that ATP-activated P2 receptors decrease tumor growth and increase apoptosis in diverse types of cancers (Hopfner et al, 1998;Wang et al, 2004;White and Burnstock, 2006). Conversely, extracellular ATP activates P2 receptors followed by increases intracellular calcium and cell proliferation of MCF-7 cells, which is supported by ATP acting as a promoter of cell proliferation and growth (Dixon et al, 1997;Wagstaff et al, 2000). Therefore, further studies on the mechanisms by which raloxifene inhibits P2 receptor-mediated signaling are needed.…”

Section: Raloxifene Induces Autophagy Via Ampk Activationmentioning

confidence: 87%

Raloxifene Induces Autophagy-Dependent Cell Death in Breast Cancer Cells via the Activation of AMP-Activated Protein Kinase

Kim¹,

Kim²,

Cho³

et al. 2015

Molecules and Cells

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Raloxifene is a selective estrogen receptor modulator (SERM) that binds to the estrogen receptor (ER), and exhibits potent anti-tumor and autophagy-inducing effects in breast cancer cells. However, the mechanism of raloxifeneinduced cell death and autophagy is not well-established. So, we analyzed mechanism underlying death and autophagy induced by raloxifene in MCF-7 breast cancer cells. Our current study demonstrates that raloxifene induces autophagy via the activation of AMPK by sensing decreases in ATP, and that the overactivation of autophagy promotes cell death and thereby mediates the anti-cancer effects of raloxifene in breast cancer cells.

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“…If no signal was apparent after 5 min, goat anti-mouse or anti-rabbit antisera were added after washing to increase the level of Trop-2 cross-linking. Adenosine trisphosphate (ATP) (Sigma) was mostly used at a final concentration of 5 µM (Dixon et al, 1997;Popper and Batra, 1993). Measured 340/380 nm ratio values were then converted to free calcium concentration (Bizzarri and Corda, 1994).…”

Section: Measurement Of Cytosolic Ca 2ϩmentioning

confidence: 99%

“…Cytosolic Ca 2ϩ plays an important role in the regulation of the differentiated function of several nucleated cell types (Tsien and Tsien, 1990;Meldolesi et al, 1991). Importantly, it participates in the regulation of the cell cycle in proliferating cells and of tumor cells in particular (Dixon et al, 1997). Thus, it was of interest to investigate whether Trop-2/EGP-1/GA733-1 could mediate an intracelluar calcium signaling.…”

mentioning

confidence: 99%

Human TROP-2 is a tumor-associated calcium signal transducer

et al. 1998

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Trop‐2/EGP‐1/GA733‐1 is a recently identified cell surface glycoprotein highly expressed by human carcinomas. The cytoplasmic tail of Trop‐2 possesses potential serine and tyrosine phosphorylation sites and a phosphatidyl‐inositol binding consensus sequence. Thus, we investigated whether Trop‐2 might be a functional signaling molecule. Using the fluorescent probe Fura‐2, we assayed the cytoplasmic calcium levels in human cancer cells stimulated with anti‐Trop‐2 or control antibodies. Three anti‐Trop‐2 MAbs, Rs7‐7G11, MOv16 and 162‐46.2 specifically induced a transient intracellular calcium level increment in up to 40% of the experiments performed. Polyclonal antisera recognizing recombinant Trop‐2 molecules possessed a much lower stimulation efficiency. The average latency of antibody‐induced Ca2+ rise for OvCa‐432 cells was 64 ± 26 sec. Internal Ca2+ concentrations reached peaks of 190 ± 24 nM vs<0R>. basal levels of 61 ± 4 nM and returned to baseline within 193 ± 37 sec. Similar values were obtained in MCF‐7 cells. For comparison, stimulation of P2‐purinergic receptors on MCF‐7 and OvCa‐432 cells induced a Ca2+ rise in most cases, leading to average internal Ca2+ concentrations of 297 ± 41 and 391 ± 39 nM, respectively. Our findings show that Trop‐2 transduces an intracellular calcium signal, are consistent with the hypothesis that it acts as a cell surface receptor and support a search for a physiological ligand. Int. J. Cancer 76:671–676, 1998.© 1998 Wiley‐Liss, Inc.

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Extracellular nucleotides stimulate proliferation in MCF-7 breast cancer cells via P2-purinoceptors

Cited by 79 publications

References 35 publications

Role of ATP in DNA synthesis of renal proximal tubule cells: involvement of calcium, MAPKs, and CDKs

Role of ATP in DNA synthesis of renal proximal tubule cells: involvement of calcium, MAPKs, and CDKs

Raloxifene Induces Autophagy-Dependent Cell Death in Breast Cancer Cells via the Activation of AMP-Activated Protein Kinase

Human TROP-2 is a tumor-associated calcium signal transducer

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