Adenosine arrests breast cancer cell motility by A3 receptor stimulation

Purinergic Signal. 2016 Dec;12(4):673-685. doi: 10.1007/s11302-016-9531-6. Epub 2016 Aug 30.

Abstract

In neutrophils, adenosine triphosphate (ATP) release and autocrine purinergic signaling regulate coordinated cell motility during chemotaxis. Here, we studied whether similar mechanisms regulate the motility of breast cancer cells. While neutrophils and benign human mammary epithelial cells (HMEC) form a single leading edge, MDA-MB-231 breast cancer cells possess multiple leading edges enriched with A3 adenosine receptors. Compared to HMEC, MDA-MB-231 cells overexpress the ectonucleotidases ENPP1 and CD73, which convert extracellular ATP released by the cells to adenosine that stimulates A3 receptors and promotes cell migration with frequent directional changes. However, exogenous adenosine added to breast cancer cells or the A3 receptor agonist IB-MECA dose-dependently arrested cell motility by simultaneous stimulation of multiple leading edges, doubling cell surface areas and significantly reducing migration velocity by up to 75 %. We conclude that MDA-MB-231 cells, HMEC, and neutrophils differ in the purinergic signaling mechanisms that regulate their motility patterns and that the subcellular distribution of A3 adenosine receptors in MDA-MB-231 breast cancer cells contributes to dysfunctional cell motility. These findings imply that purinergic signaling mechanisms may be potential therapeutic targets to interfere with the motility of breast cancer cells in order to reduce the spread of cancer cells and the risk of metastasis.

Keywords: ATP; Adenosine; Adenosine receptor; Breast cancer; Cell motility; Purinergic signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Purinergic P1 Receptor Agonists / pharmacology*
  • Receptor, Adenosine A3 / metabolism*
  • Signal Transduction / drug effects

Substances

  • Purinergic P1 Receptor Agonists
  • Receptor, Adenosine A3
  • N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine
  • Adenosine