K ca 3.1 Activation Via P2y 2 Purinergic Receptors Promotes Human Ovarian Cancer Cell (Skov-3) Migration

Sci Rep. 2017 Jun 28;7(1):4340. doi: 10.1038/s41598-017-04292-6.

Abstract

Disorders in cell signaling mediated by ATP or histamine, activating specific membrane receptors, have been frequently associated with tumorigenesis. Among the elements of response to purinergic (and histaminergic) signaling, ion channel activation controls essential cellular processes in cancer, such as cell proliferation, motility, and death. Here, we studied the effects that ATP had on electrical properties of human ovarian adenocarcinoma cells named SKOV-3. ATP caused increase in intracellular Ca2+ concentration ([Ca2+]i) and, concurrently, it evoked a complex electrical response with a conspicuous outward component. This current was generated through P2Y2 receptor activation and opening of K+ channels, KCa3.1, as indicated by electrophysiological and pharmacological analysis, as well as by immunodetection and specific silencing of P2Y2 or KCa3.1 gene by esiRNA transfection. Low µM ATP concentration increased SKOV-3 cell migration, which was strongly inhibited by KCa3.1 channel blockers and by esiRNA-generated P2Y2 or KCa3.1 downregulation. Finally, in human ovarian tumors, the P2Y2 and KCa3.1 proteins are expressed and co-localized in neoplastic cells. Thus, stimulation of P2Y2 receptors expressed in SKOV-3 cells promotes motility through KCa3.1 activation. Since P2Y2 and KCa3.1 are co-expressed in primary tumors, our findings suggest that they may play a role in cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression
  • Gene Silencing
  • Humans
  • Intermediate-Conductance Calcium-Activated Potassium Channels / agonists
  • Intermediate-Conductance Calcium-Activated Potassium Channels / genetics
  • Intermediate-Conductance Calcium-Activated Potassium Channels / metabolism*
  • Ion Channel Gating*
  • Ions / metabolism
  • Membrane Potentials
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Potassium Channel Blockers / pharmacology
  • RNA, Small Interfering / genetics
  • Receptors, Purinergic P2Y2 / metabolism*

Substances

  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • Ions
  • KCNN4 protein, human
  • Potassium Channel Blockers
  • RNA, Small Interfering
  • Receptors, Purinergic P2Y2
  • Adenosine Triphosphate
  • Calcium