Pivotal role of Akt activation in mitochondrial protection and cell survival by poly(ADP-ribose)polymerase-1 inhibition in oxidative stress

Antal Tapodi, B. Debreceni, Katalin Hanto, Z. Bognár, I. Wittmann, F. Gallyas, Gabor Varbiro, B. Sümegi

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

According to the classical view, the cytoprotective effect of inhibitors of poly( ADP-ribose)polymerase(PARP) in oxidative stress was based on the prevention of NAD+ and ATP depletion, thus the attenuation of necrosis. Our previous data on PARP inhibitors in an inflammatory model suggested that PARP-catalyzed ADP-ribosylations may affect signaling pathways, which can play a significant role in cell survival. To clarify the molecular mechanism of cytoprotection, PARP activity was inhibited pharmacologically by suppressing PARP-1 expression by a small interfering RNA (siRNA) technique or by transdominantly expressing the N-terminal DNA-binding domain of PARP-1 (PARP-DBD) in cultured cells. Cell survival, activation of the phosphatidylinositol 3-kinase (PI3-kinase)/ Akt system, and the preservation of mitochondrial membrane potential were studied in hydrogen peroxide-treated WRL-68 cells. Our data showed that suppression of the single-stranded DNA break-induced PARP-1 activation by pharmacological inhibitor, siRNA, or by the transdominant expression of PARP-DBD protected cells from oxidative stress and induced the phosphorylation and activation of Akt. Furthermore, prevention of Akt activation by inhibiting PI3-kinase counteracted the cytoprotective effect of PARP inhibition. Microscopy data showed that PARP inhibition-induced Akt activation was responsible for protection of mitochondria in oxidative stress because PI3-kinase inhibitors diminished the protective effect of PARP inhibition. Similarly, Src kinase inhibitors, which decrease Akt phosphorylation, also counteracted the protection of mitochondrial membrane potential supporting the pivotal role of Akt in cytoprotection. These data together with the finding that PARP inhibition in the absence of oxidative stress induced the phosphorylation and activation of Akt indicate that PARP inhibition-induced Akt activation is dominantly responsible for the cytoprotection in oxidative stress.

Original languageEnglish
Pages (from-to)35767-35775
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number42
DOIs
Publication statusPublished - Oct 21 2005

Fingerprint

Oxidative stress
Poly(ADP-ribose) Polymerases
Cell Survival
Oxidative Stress
Chemical activation
Cells
Phosphatidylinositol 3-Kinase
Cytoprotection
Phosphorylation
Mitochondrial Membrane Potential
Small Interfering RNA
Poly (ADP-Ribose) Polymerase-1
Single-Stranded DNA Breaks
src-Family Kinases
Membranes
NAD
Adenosine Diphosphate
Hydrogen Peroxide
Mitochondria
Microscopy

ASJC Scopus subject areas

  • Biochemistry

Cite this

@article{59b901ab9fa9493683c14c50e804f3eb,
title = "Pivotal role of Akt activation in mitochondrial protection and cell survival by poly(ADP-ribose)polymerase-1 inhibition in oxidative stress",
abstract = "According to the classical view, the cytoprotective effect of inhibitors of poly( ADP-ribose)polymerase(PARP) in oxidative stress was based on the prevention of NAD+ and ATP depletion, thus the attenuation of necrosis. Our previous data on PARP inhibitors in an inflammatory model suggested that PARP-catalyzed ADP-ribosylations may affect signaling pathways, which can play a significant role in cell survival. To clarify the molecular mechanism of cytoprotection, PARP activity was inhibited pharmacologically by suppressing PARP-1 expression by a small interfering RNA (siRNA) technique or by transdominantly expressing the N-terminal DNA-binding domain of PARP-1 (PARP-DBD) in cultured cells. Cell survival, activation of the phosphatidylinositol 3-kinase (PI3-kinase)/ Akt system, and the preservation of mitochondrial membrane potential were studied in hydrogen peroxide-treated WRL-68 cells. Our data showed that suppression of the single-stranded DNA break-induced PARP-1 activation by pharmacological inhibitor, siRNA, or by the transdominant expression of PARP-DBD protected cells from oxidative stress and induced the phosphorylation and activation of Akt. Furthermore, prevention of Akt activation by inhibiting PI3-kinase counteracted the cytoprotective effect of PARP inhibition. Microscopy data showed that PARP inhibition-induced Akt activation was responsible for protection of mitochondria in oxidative stress because PI3-kinase inhibitors diminished the protective effect of PARP inhibition. Similarly, Src kinase inhibitors, which decrease Akt phosphorylation, also counteracted the protection of mitochondrial membrane potential supporting the pivotal role of Akt in cytoprotection. These data together with the finding that PARP inhibition in the absence of oxidative stress induced the phosphorylation and activation of Akt indicate that PARP inhibition-induced Akt activation is dominantly responsible for the cytoprotection in oxidative stress.",
author = "Antal Tapodi and B. Debreceni and Katalin Hanto and Z. Bogn{\'a}r and I. Wittmann and F. Gallyas and Gabor Varbiro and B. S{\"u}megi",
year = "2005",
month = "10",
day = "21",
doi = "10.1074/jbc.M507075200",
language = "English",
volume = "280",
pages = "35767--35775",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "42",

}

TY - JOUR

T1 - Pivotal role of Akt activation in mitochondrial protection and cell survival by poly(ADP-ribose)polymerase-1 inhibition in oxidative stress

AU - Tapodi, Antal

AU - Debreceni, B.

AU - Hanto, Katalin

AU - Bognár, Z.

AU - Wittmann, I.

AU - Gallyas, F.

AU - Varbiro, Gabor

AU - Sümegi, B.

PY - 2005/10/21

Y1 - 2005/10/21

N2 - According to the classical view, the cytoprotective effect of inhibitors of poly( ADP-ribose)polymerase(PARP) in oxidative stress was based on the prevention of NAD+ and ATP depletion, thus the attenuation of necrosis. Our previous data on PARP inhibitors in an inflammatory model suggested that PARP-catalyzed ADP-ribosylations may affect signaling pathways, which can play a significant role in cell survival. To clarify the molecular mechanism of cytoprotection, PARP activity was inhibited pharmacologically by suppressing PARP-1 expression by a small interfering RNA (siRNA) technique or by transdominantly expressing the N-terminal DNA-binding domain of PARP-1 (PARP-DBD) in cultured cells. Cell survival, activation of the phosphatidylinositol 3-kinase (PI3-kinase)/ Akt system, and the preservation of mitochondrial membrane potential were studied in hydrogen peroxide-treated WRL-68 cells. Our data showed that suppression of the single-stranded DNA break-induced PARP-1 activation by pharmacological inhibitor, siRNA, or by the transdominant expression of PARP-DBD protected cells from oxidative stress and induced the phosphorylation and activation of Akt. Furthermore, prevention of Akt activation by inhibiting PI3-kinase counteracted the cytoprotective effect of PARP inhibition. Microscopy data showed that PARP inhibition-induced Akt activation was responsible for protection of mitochondria in oxidative stress because PI3-kinase inhibitors diminished the protective effect of PARP inhibition. Similarly, Src kinase inhibitors, which decrease Akt phosphorylation, also counteracted the protection of mitochondrial membrane potential supporting the pivotal role of Akt in cytoprotection. These data together with the finding that PARP inhibition in the absence of oxidative stress induced the phosphorylation and activation of Akt indicate that PARP inhibition-induced Akt activation is dominantly responsible for the cytoprotection in oxidative stress.

AB - According to the classical view, the cytoprotective effect of inhibitors of poly( ADP-ribose)polymerase(PARP) in oxidative stress was based on the prevention of NAD+ and ATP depletion, thus the attenuation of necrosis. Our previous data on PARP inhibitors in an inflammatory model suggested that PARP-catalyzed ADP-ribosylations may affect signaling pathways, which can play a significant role in cell survival. To clarify the molecular mechanism of cytoprotection, PARP activity was inhibited pharmacologically by suppressing PARP-1 expression by a small interfering RNA (siRNA) technique or by transdominantly expressing the N-terminal DNA-binding domain of PARP-1 (PARP-DBD) in cultured cells. Cell survival, activation of the phosphatidylinositol 3-kinase (PI3-kinase)/ Akt system, and the preservation of mitochondrial membrane potential were studied in hydrogen peroxide-treated WRL-68 cells. Our data showed that suppression of the single-stranded DNA break-induced PARP-1 activation by pharmacological inhibitor, siRNA, or by the transdominant expression of PARP-DBD protected cells from oxidative stress and induced the phosphorylation and activation of Akt. Furthermore, prevention of Akt activation by inhibiting PI3-kinase counteracted the cytoprotective effect of PARP inhibition. Microscopy data showed that PARP inhibition-induced Akt activation was responsible for protection of mitochondria in oxidative stress because PI3-kinase inhibitors diminished the protective effect of PARP inhibition. Similarly, Src kinase inhibitors, which decrease Akt phosphorylation, also counteracted the protection of mitochondrial membrane potential supporting the pivotal role of Akt in cytoprotection. These data together with the finding that PARP inhibition in the absence of oxidative stress induced the phosphorylation and activation of Akt indicate that PARP inhibition-induced Akt activation is dominantly responsible for the cytoprotection in oxidative stress.

UR - http://www.scopus.com/inward/record.url?scp=27444446861&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27444446861&partnerID=8YFLogxK

U2 - 10.1074/jbc.M507075200

DO - 10.1074/jbc.M507075200

M3 - Article

C2 - 16115861

AN - SCOPUS:27444446861

VL - 280

SP - 35767

EP - 35775

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 42

ER -