PARP inhibition protects mitochondria and reduces ROS production via PARP-1-ATF4-MKP-1-MAPK retrograde pathway

Eniko Hocsak, Viktor Szabo, Nikoletta Kalman, Csenge Antus, Anna Cseh, Katalin Sumegi, Krisztian Eros, Z. Hegedűs, F. Gallyas, B. Sümegi, B. Rácz

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18 Citations (Scopus)

Abstract

Oxidative stress induces DNA breaks and PARP-1 activation which initiates mitochondrial reactive oxygen species (ROS) production and cell death through pathways not yet identified. Here, we show the mechanism by which PARP-1 influences these processes via PARylation of activating transcription factor-4 (ATF4) responsible for MAP kinase phosphatase-1 (MKP-1) expression and thereby regulates MAP kinases. PARP inhibitor, or silencing, of PARP induced MKP-1 expression by ATF4-dependent way, and inactivated JNK and p38 MAP kinases. Additionally, it induced ATF4 expression and binding to cAMP-response element (CRE) leading to MKP-1 expression and the inactivation of MAP kinases. In contrast, PARP-1 activation induced the PARylation of ATF4 and reduced its binding to CRE sequence in vitro. CHIP-qPCR analysis showed that PARP inhibitor increased the ATF4 occupancy at the initiation site of MKP-1. In oxidative stress, PARP inhibition reduced ROS-induced cell death, suppressed mitochondrial ROS production and protected mitochondrial membrane potential on an ATF4 and MKP-1 dependent way. Basically identical results were obtained in WRL-68, A-549 and T24/83 human cell lines indicating that the aforementioned mechanism can be universal. Here, we provide the first description of PARP-1-ATF4-MKP-1-JNK/p38 MAPK retrograde pathway, which is responsible for the regulation of mitochondrial integrity, ROS production and cell death in oxidative stress, and may represent a new mechanism of PARP in cancer therapy since cancer stem cells development is JNK-dependent.

Original languageEnglish
Pages (from-to)770-784
Number of pages15
JournalFree Radical Biology and Medicine
Volume108
DOIs
Publication statusPublished - Jul 1 2017

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Keywords

  • ATF4
  • Cancer
  • CREB
  • CREB2
  • Dusp1
  • JNK
  • MKP-1
  • Oxidative stress
  • P38 MAPK
  • PARP-1 inhibition
  • ROS
  • Stem cells

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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