ROS-induced store-operated Ca2+ entry coupled to PARP-1 hyperactivation is independent of PARG activity in necrotic cell death

Frances M. Munoz, Fengjiao Zhang, Argel Islas-Robles, Serrine Lau, Terrence Monks

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

2,3,5-tris(Glutathion-S-yl)hydroquinone, a potent nephrotoxic and nephrocarcinogenic metabolite of benzene and hydroquinone, generates reactive oxygen species (ROS) causing DNA strand breaks and the subsequent activation of DNA repair enzymes, including poly(ADP-ribose) polymerase (PARP)-1. Under robust oxidative DNA damage, PARP-1 is hyperactivated, resulting in the depletion of NAD+ and ATP with accompanying elevations in intracellular calcium concentrations (iCa2+), and ultimately necrotic cell death. The role of Ca2+ during PARP-dependent necrotic cell death remains unclear. We therefore sought to determine the relationship between Ca2+ and PARP-1 during ROS-induced necrotic cell death in human renal proximal tubule epithelial cells (HK-2). Our experiments suggest that store-operated Ca2+ channel (SOC) entry contributes to the coupling of PARP-1 activation to increases in iCa2+ during ROS-induced cell death. Poly(ADP-ribose)glycohydrolase (PARG), which catalyzes the degradation of PARs to yield free ADP-ribose (ADPR), is known to activate Ca2+ channels such as TRPM2. However, siRNA knockdown of PARG did not restore cell viability, indicating that free ADPR is not responsible for SOC activation in HK-2 cells. The data indicate that PARP-1 and iCa2+ are coupled through activation of SOC mediated Ca2+ entry in an apparently ADPR-independent fashion; alternative PAR-mediated signaling likely contributes to PARP-dependent necrotic cell death, perhaps via PAR-mediated signaling proteins that regulate iCa2+ homeostasis.

Original languageEnglish (US)
Article numberkfx106
Pages (from-to)444-453
Number of pages10
JournalToxicological Sciences
Volume158
Issue number2
DOIs
Publication statusPublished - Aug 1 2017

    Fingerprint

Keywords

  • 2,3,5-tris(glutathione-S-yl)hydroquinone
  • HK-2 cells
  • PARylation
  • Poly(ADP-ribose)glycohydrolase
  • Poly(ADP-ribose)polymerase-1
  • Store-operated calcium channel entry

ASJC Scopus subject areas

  • Toxicology

Cite this