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Extracellular nucleotides inhibit growth of human oesophageal cancer cells via P2Y(2)-receptors.

Maaser K, Höpfner M, Kap H, Sutter AP, Barthel B, von Lampe B, Zeitz M, Scherübl H - Br. J. Cancer (2002)

Bottom Line: The rank order of potency was ATP=UTP>ATP gamma S>ADP=UDP. 2-methylthio-ATP and alpha,beta-methylene-ATP had no effects on [Ca(2+)](i).Moreover, the phospholipase C inhibitor U73122 dose-dependently reduced the ATP triggered [Ca(2+)](i) signal.P2Y(2)-receptors are involved in the antiproliferative actions of extracellular nucleotides.

View Article: PubMed Central - PubMed

Affiliation: Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, Benjamin Franklin Clinics, Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.

ABSTRACT
Extracellular ATP is known to inhibit growth of various tumours by activating specific purinergic receptors (P2-receptors). Since the therapy of advanced oesophageal cancer is unsatisfying, new therapeutic approaches are mandatory. Here, we investigated the functional expression and potential antiproliferative effects of P2-purinergic receptors in human oesophageal cancer cells. Prolonged incubation of primary cell cultures of human oesophageal cancers as well as of the squamous oesophageal cancer cell line Kyse-140 with ATP or its stable analogue ATP gamma S dose-dependently inhibited cell proliferation. This was due to both an induction of apoptosis and cell cycle arrest. The expression of P2-receptors was examined by RT-PCR, immunocytochemistry, and [Ca(2+)](i)-imaging. Application of various extracellular nucleotides dose-dependently increased [Ca(2+)](i). The rank order of potency was ATP=UTP>ATP gamma S>ADP=UDP. 2-methylthio-ATP and alpha,beta-methylene-ATP had no effects on [Ca(2+)](i). Complete cross-desensitization between ATP and UTP was observed. Moreover, the phospholipase C inhibitor U73122 dose-dependently reduced the ATP triggered [Ca(2+)](i) signal. The pharmacological features strongly suggest the functional expression of G-protein coupled P2Y(2)-receptors in oesophageal squamous cancer cells. P2Y(2)-receptors are involved in the antiproliferative actions of extracellular nucleotides. Thus, P2Y(2)-receptors are promising target proteins for innovative approaches in oesophageal cancer therapy.

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Antiproliferative and cell cycle effects of nucleotides. (A) Extracellular ATP (⋄) and ATPγS (□) significantly decreased the cell number of Kyse-140 cells after 3 days of incubation in a dose-dependent manner (P<0.05 for 100–500 μM). In contrast, 2MeSATP (○) or adenosine (Δ) showed no or minor effects. The respective antiproliferative effects are given as the percentage of cells of the untreated controls (=100%). Means±s.e.m. of four independent experiments are shown. (B) After 24 h of incubation both ATP and ATPγS altered the proportion of cells in the G1/G0-phase (white columns), S-phase (hatched columns), and G2/M-phase (black columns) of the cell cycle. Means±s.e.m. of six independent experiments are shown.
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fig1: Antiproliferative and cell cycle effects of nucleotides. (A) Extracellular ATP (⋄) and ATPγS (□) significantly decreased the cell number of Kyse-140 cells after 3 days of incubation in a dose-dependent manner (P<0.05 for 100–500 μM). In contrast, 2MeSATP (○) or adenosine (Δ) showed no or minor effects. The respective antiproliferative effects are given as the percentage of cells of the untreated controls (=100%). Means±s.e.m. of four independent experiments are shown. (B) After 24 h of incubation both ATP and ATPγS altered the proportion of cells in the G1/G0-phase (white columns), S-phase (hatched columns), and G2/M-phase (black columns) of the cell cycle. Means±s.e.m. of six independent experiments are shown.

Mentions: ATP is known to inhibit cancer growth in various tumour models (Agteresch et al, 1999). However, its role in growth control of human oesophageal cancer remains elusive. To investigate putative growth modulating effects of extracellular nucleotides in oesophageal carcinoma cells, cell proliferation assays were performed with Kyse-140 cells. For these experiments ATP, the hydrolysis resistant ATP derivative ATPγS, adenosine, and 2MeSATP were used ( Figure 1AFigure 1


Extracellular nucleotides inhibit growth of human oesophageal cancer cells via P2Y(2)-receptors.

Maaser K, Höpfner M, Kap H, Sutter AP, Barthel B, von Lampe B, Zeitz M, Scherübl H - Br. J. Cancer (2002)

Antiproliferative and cell cycle effects of nucleotides. (A) Extracellular ATP (⋄) and ATPγS (□) significantly decreased the cell number of Kyse-140 cells after 3 days of incubation in a dose-dependent manner (P<0.05 for 100–500 μM). In contrast, 2MeSATP (○) or adenosine (Δ) showed no or minor effects. The respective antiproliferative effects are given as the percentage of cells of the untreated controls (=100%). Means±s.e.m. of four independent experiments are shown. (B) After 24 h of incubation both ATP and ATPγS altered the proportion of cells in the G1/G0-phase (white columns), S-phase (hatched columns), and G2/M-phase (black columns) of the cell cycle. Means±s.e.m. of six independent experiments are shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2375265&req=5

fig1: Antiproliferative and cell cycle effects of nucleotides. (A) Extracellular ATP (⋄) and ATPγS (□) significantly decreased the cell number of Kyse-140 cells after 3 days of incubation in a dose-dependent manner (P<0.05 for 100–500 μM). In contrast, 2MeSATP (○) or adenosine (Δ) showed no or minor effects. The respective antiproliferative effects are given as the percentage of cells of the untreated controls (=100%). Means±s.e.m. of four independent experiments are shown. (B) After 24 h of incubation both ATP and ATPγS altered the proportion of cells in the G1/G0-phase (white columns), S-phase (hatched columns), and G2/M-phase (black columns) of the cell cycle. Means±s.e.m. of six independent experiments are shown.
Mentions: ATP is known to inhibit cancer growth in various tumour models (Agteresch et al, 1999). However, its role in growth control of human oesophageal cancer remains elusive. To investigate putative growth modulating effects of extracellular nucleotides in oesophageal carcinoma cells, cell proliferation assays were performed with Kyse-140 cells. For these experiments ATP, the hydrolysis resistant ATP derivative ATPγS, adenosine, and 2MeSATP were used ( Figure 1AFigure 1

Bottom Line: The rank order of potency was ATP=UTP>ATP gamma S>ADP=UDP. 2-methylthio-ATP and alpha,beta-methylene-ATP had no effects on [Ca(2+)](i).Moreover, the phospholipase C inhibitor U73122 dose-dependently reduced the ATP triggered [Ca(2+)](i) signal.P2Y(2)-receptors are involved in the antiproliferative actions of extracellular nucleotides.

View Article: PubMed Central - PubMed

Affiliation: Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, Benjamin Franklin Clinics, Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.

ABSTRACT
Extracellular ATP is known to inhibit growth of various tumours by activating specific purinergic receptors (P2-receptors). Since the therapy of advanced oesophageal cancer is unsatisfying, new therapeutic approaches are mandatory. Here, we investigated the functional expression and potential antiproliferative effects of P2-purinergic receptors in human oesophageal cancer cells. Prolonged incubation of primary cell cultures of human oesophageal cancers as well as of the squamous oesophageal cancer cell line Kyse-140 with ATP or its stable analogue ATP gamma S dose-dependently inhibited cell proliferation. This was due to both an induction of apoptosis and cell cycle arrest. The expression of P2-receptors was examined by RT-PCR, immunocytochemistry, and [Ca(2+)](i)-imaging. Application of various extracellular nucleotides dose-dependently increased [Ca(2+)](i). The rank order of potency was ATP=UTP>ATP gamma S>ADP=UDP. 2-methylthio-ATP and alpha,beta-methylene-ATP had no effects on [Ca(2+)](i). Complete cross-desensitization between ATP and UTP was observed. Moreover, the phospholipase C inhibitor U73122 dose-dependently reduced the ATP triggered [Ca(2+)](i) signal. The pharmacological features strongly suggest the functional expression of G-protein coupled P2Y(2)-receptors in oesophageal squamous cancer cells. P2Y(2)-receptors are involved in the antiproliferative actions of extracellular nucleotides. Thus, P2Y(2)-receptors are promising target proteins for innovative approaches in oesophageal cancer therapy.

Show MeSH
Related in: MedlinePlus