Skip to Content
Merck
  • Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis.

Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis.

Oncogene (2014-05-20)
J Z Zhou, M A Riquelme, X Gao, L G Ellies, L Z Sun, J X Jiang
ABSTRACT

Extracellular ATP has been shown to either inhibit or promote cancer growth and migration; however, the mechanism underlying this discrepancy remained elusive. Here we demonstrate the divergent roles of ATP and adenosine released by bone osteocytes on breast cancers. We showed that conditioned media (CM) collected from osteocytes treated with alendronate (AD), a bisphosphonate drug, inhibited the migration of human breast cancer MDA-MB-231 cells. Removal of the extracellular ATP by apyrase in CM abolished this effect, suggesting the involvement of ATP. ATP exerted its inhibitory effect through the activation of purinergic P2X receptor signaling in breast cancer cells evidenced by the attenuation of the inhibition by an antagonist, oxidized ATP, as well as knocking down P2X7 with small interfering RNA (siRNA), and the inhibition of migration by an agonist, BzATP. Intriguingly, ATP had a biphasic effect on breast cancer cells-lower dosage inhibited but higher dosage promoted its migration. The stimulatory effect on migration was blocked by an adenosine receptor antagonist, MRS1754, ARL67156, an ecto-ATPase inhibitor, and A2A receptor siRNA, suggesting that in contrast to ATP, adenosine, a metabolic product of ATP, promoted migration of breast cancer cells. Consistently, non-hydrolyzable ATP, ATPγS, only inhibited but did not promote cancer cell migration. ATP also had a similar inhibitory effect on the Py8119 mouse mammary carcinoma cells; however, adenosine had no effect owing to the absence of the A2A receptor. Consistently, ATPγS inhibited, whereas adenosine promoted anchorage-independent growth of MDA-MB-231 cells. Our in vivo xenograft study showed a significant delay of tumor growth with the treatment of ATPγS. Moreover, the extent of bone metastasis in a mouse intratibial model was significantly reduced with the treatment of ATPγS. Together, our results suggest the distinct roles of ATP and adenosine released by osteocytes and the activation of corresponding receptors P2X7 and A2A signaling on breast cancer cell growth, migration and bone metastasis.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Acetonitrile solution, contains 10.0% acetone, 0.05% formic acid, 40.0% 2-propanol
Sigma-Aldrich
Acetonitrile solution, contains 0.05 % (w/v) ammonium formate, 5 % (v/v) water, 0.1 % (v/v) formic acid, suitable for HPLC
Sigma-Aldrich
Acetonitrile solution, contains 0.05 % (v/v) trifluoroacetic acid
Sigma-Aldrich
Acetonitrile solution, contains 0.1 % (v/v) trifluoroacetic acid, suitable for HPLC
Sigma-Aldrich
Acetonitrile solution, contains 0.1 % (v/v) formic acid, suitable for HPLC
Supelco
DL-Dithiothreitol solution, 1 M in H2O
Sigma-Aldrich
D-Luciferin, synthetic, BioXtra, ≥99% (HPLC)
Sigma-Aldrich
D-Luciferin, synthetic
Sigma-Aldrich
DL-Dithiothreitol solution, BioUltra, for molecular biology, ~1 M in H2O
Supelco
Residual Solvent - Acetonitrile, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Acetonitrile, ≥99.8%, for residue analysis, JIS 300
Sigma-Aldrich
Acetonitrile, ≥99.8%, for residue analysis, JIS 1000
Sigma-Aldrich
Diethylamine, SAJ special grade, ≥99.0%
Sigma-Aldrich
Diethylamine, SAJ first grade, ≥98.0%
Sigma-Aldrich
Acetonitrile, ≥99.8%, suitable for HPLC
Sigma-Aldrich
Acetonitrile, SAJ first grade, ≥99.0%
Sigma-Aldrich
Acetonitrile, JIS special grade, ≥99.5%
Sigma-Aldrich
Acetonitrile, for chromatography
Sigma-Aldrich
Acetonitrile, for residue analysis, JIS 5000
Sigma-Aldrich
Acetonitrile, HPLC Plus, ≥99.9%, poly-coated bottles
Sigma-Aldrich
Acetonitrile, electronic grade, 99.999% trace metals basis
Supelco
Adenosine, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Diethylamine, puriss. p.a., ≥99.5% (GC)
Sigma-Aldrich
Acetonitrile, ≥99.5%, ACS reagent
Sigma-Aldrich
Acetonitrile, anhydrous, 99.8%
Sigma-Aldrich
Diethylamine, purified by redistillation, 99.5%
Sigma-Aldrich
Adenosine
Supelco
Acetonitrile, HPLC grade, ≥99.93%
Sigma-Aldrich
Diethylamine, ≥99.5%
Sigma-Aldrich
Adenosine, ≥99%