Protective effect of the poly(ADP-ribose) polymerase inhibitor PJ34 on mitochondrial depolarization-mediated cell death in hepatocellular carcinoma cells involves attenuation of c-Jun N-terminal kinase-2 and protein kinase B/Akt activation

Balazs Radnai, Csenge Antus, B. Rácz, P. Engelmann, Janos K. Priber, Zsuzsanna Tucsek, Balazs Veres, Zsuzsanna Turi, T. Lóránd, B. Sümegi, F. Gallyas

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: 2,4-Dimethoxyphenyl-E-4-arylidene-3-isochromanone (IK11) was previously described to induce apoptotic death of A431 tumor cells. In this report, we investigated the molecular action of IK11 in the HepG2 human hepatocellular carcinoma cell line to increase our knowledge of the role of poly (ADP-ribose)-polymerase (PARP), protein kinase B/Akt and mitogen activated protein kinase (MAPK) activation in the survival and death of tumor cells and to highlight the possible role of PARP-inhibitors in co-treatments with different cytotoxic agents in cancer therapy.Results: We found that sublethal concentrations of IK11 prevented proliferation, migration and entry of the cells into their G2 phase. At higher concentrations, IK11 induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, activation of c-Jun N-terminal kinase 2 (JNK2), and substantial loss of HepG2 cells. ROS production appeared marginal in mediating the cytotoxicity of IK11 since N-acetyl cysteine was unable to prevent it. However, the PARP inhibitor PJ34, although not a ROS scavenger, strongly inhibited both IK11-induced ROS production and cell death. JNK2 activation seemed to be a major mediator of the effect of IK11 since inhibition of JNK resulted in a substantial cytoprotection while inhibitors of the other kinases failed to do so. Inhibition of Akt slightly diminished the effect of IK11, while the JNK and Akt inhibitor and ROS scavenger trans-resveratrol completely protected against it.Conclusions: These results indicate significant involvement of PARP, a marginal role of ROS and a pro-apoptotic role of Akt in this system, and raise attention to a novel mechanism that should be considered when cancer therapy is augmented with PARP-inhibition, namely the cytoprotection by inhibition of JNK2.

Original languageEnglish
Article number34
JournalMolecular Cancer
Volume11
DOIs
Publication statusPublished - May 14 2012

Fingerprint

Mitogen-Activated Protein Kinase 9
Proto-Oncogene Proteins c-akt
Hepatocellular Carcinoma
Reactive Oxygen Species
Cell Death
Poly(ADP-ribose) Polymerases
Phosphotransferases
Cytoprotection
Neoplasms
G2 Phase
Cytotoxins
Hep G2 Cells
Mitochondrial Membranes
Mitogen-Activated Protein Kinases
Cell Movement
Cysteine
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Poly(ADP-ribose) Polymerase Inhibitors
Cell Line
Survival

Keywords

  • c-Jun N-terminal kinase (JNK)
  • Mitochondrial depolarization
  • Mitogen activated protein kinase (MAPK)
  • Poly(ADP-ribose)-polymerase (PARP)
  • Protein kinase B (PKB/Akt)

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Oncology

Cite this

@article{a88442e9e8db4591ad48054909782948,
title = "Protective effect of the poly(ADP-ribose) polymerase inhibitor PJ34 on mitochondrial depolarization-mediated cell death in hepatocellular carcinoma cells involves attenuation of c-Jun N-terminal kinase-2 and protein kinase B/Akt activation",
abstract = "Background: 2,4-Dimethoxyphenyl-E-4-arylidene-3-isochromanone (IK11) was previously described to induce apoptotic death of A431 tumor cells. In this report, we investigated the molecular action of IK11 in the HepG2 human hepatocellular carcinoma cell line to increase our knowledge of the role of poly (ADP-ribose)-polymerase (PARP), protein kinase B/Akt and mitogen activated protein kinase (MAPK) activation in the survival and death of tumor cells and to highlight the possible role of PARP-inhibitors in co-treatments with different cytotoxic agents in cancer therapy.Results: We found that sublethal concentrations of IK11 prevented proliferation, migration and entry of the cells into their G2 phase. At higher concentrations, IK11 induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, activation of c-Jun N-terminal kinase 2 (JNK2), and substantial loss of HepG2 cells. ROS production appeared marginal in mediating the cytotoxicity of IK11 since N-acetyl cysteine was unable to prevent it. However, the PARP inhibitor PJ34, although not a ROS scavenger, strongly inhibited both IK11-induced ROS production and cell death. JNK2 activation seemed to be a major mediator of the effect of IK11 since inhibition of JNK resulted in a substantial cytoprotection while inhibitors of the other kinases failed to do so. Inhibition of Akt slightly diminished the effect of IK11, while the JNK and Akt inhibitor and ROS scavenger trans-resveratrol completely protected against it.Conclusions: These results indicate significant involvement of PARP, a marginal role of ROS and a pro-apoptotic role of Akt in this system, and raise attention to a novel mechanism that should be considered when cancer therapy is augmented with PARP-inhibition, namely the cytoprotection by inhibition of JNK2.",
keywords = "c-Jun N-terminal kinase (JNK), Mitochondrial depolarization, Mitogen activated protein kinase (MAPK), Poly(ADP-ribose)-polymerase (PARP), Protein kinase B (PKB/Akt)",
author = "Balazs Radnai and Csenge Antus and B. R{\'a}cz and P. Engelmann and Priber, {Janos K.} and Zsuzsanna Tucsek and Balazs Veres and Zsuzsanna Turi and T. L{\'o}r{\'a}nd and B. S{\"u}megi and F. Gallyas",
year = "2012",
month = "5",
day = "14",
doi = "10.1186/1476-4598-11-34",
language = "English",
volume = "11",
journal = "Molecular Cancer",
issn = "1476-4598",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Protective effect of the poly(ADP-ribose) polymerase inhibitor PJ34 on mitochondrial depolarization-mediated cell death in hepatocellular carcinoma cells involves attenuation of c-Jun N-terminal kinase-2 and protein kinase B/Akt activation

AU - Radnai, Balazs

AU - Antus, Csenge

AU - Rácz, B.

AU - Engelmann, P.

AU - Priber, Janos K.

AU - Tucsek, Zsuzsanna

AU - Veres, Balazs

AU - Turi, Zsuzsanna

AU - Lóránd, T.

AU - Sümegi, B.

AU - Gallyas, F.

PY - 2012/5/14

Y1 - 2012/5/14

N2 - Background: 2,4-Dimethoxyphenyl-E-4-arylidene-3-isochromanone (IK11) was previously described to induce apoptotic death of A431 tumor cells. In this report, we investigated the molecular action of IK11 in the HepG2 human hepatocellular carcinoma cell line to increase our knowledge of the role of poly (ADP-ribose)-polymerase (PARP), protein kinase B/Akt and mitogen activated protein kinase (MAPK) activation in the survival and death of tumor cells and to highlight the possible role of PARP-inhibitors in co-treatments with different cytotoxic agents in cancer therapy.Results: We found that sublethal concentrations of IK11 prevented proliferation, migration and entry of the cells into their G2 phase. At higher concentrations, IK11 induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, activation of c-Jun N-terminal kinase 2 (JNK2), and substantial loss of HepG2 cells. ROS production appeared marginal in mediating the cytotoxicity of IK11 since N-acetyl cysteine was unable to prevent it. However, the PARP inhibitor PJ34, although not a ROS scavenger, strongly inhibited both IK11-induced ROS production and cell death. JNK2 activation seemed to be a major mediator of the effect of IK11 since inhibition of JNK resulted in a substantial cytoprotection while inhibitors of the other kinases failed to do so. Inhibition of Akt slightly diminished the effect of IK11, while the JNK and Akt inhibitor and ROS scavenger trans-resveratrol completely protected against it.Conclusions: These results indicate significant involvement of PARP, a marginal role of ROS and a pro-apoptotic role of Akt in this system, and raise attention to a novel mechanism that should be considered when cancer therapy is augmented with PARP-inhibition, namely the cytoprotection by inhibition of JNK2.

AB - Background: 2,4-Dimethoxyphenyl-E-4-arylidene-3-isochromanone (IK11) was previously described to induce apoptotic death of A431 tumor cells. In this report, we investigated the molecular action of IK11 in the HepG2 human hepatocellular carcinoma cell line to increase our knowledge of the role of poly (ADP-ribose)-polymerase (PARP), protein kinase B/Akt and mitogen activated protein kinase (MAPK) activation in the survival and death of tumor cells and to highlight the possible role of PARP-inhibitors in co-treatments with different cytotoxic agents in cancer therapy.Results: We found that sublethal concentrations of IK11 prevented proliferation, migration and entry of the cells into their G2 phase. At higher concentrations, IK11 induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, activation of c-Jun N-terminal kinase 2 (JNK2), and substantial loss of HepG2 cells. ROS production appeared marginal in mediating the cytotoxicity of IK11 since N-acetyl cysteine was unable to prevent it. However, the PARP inhibitor PJ34, although not a ROS scavenger, strongly inhibited both IK11-induced ROS production and cell death. JNK2 activation seemed to be a major mediator of the effect of IK11 since inhibition of JNK resulted in a substantial cytoprotection while inhibitors of the other kinases failed to do so. Inhibition of Akt slightly diminished the effect of IK11, while the JNK and Akt inhibitor and ROS scavenger trans-resveratrol completely protected against it.Conclusions: These results indicate significant involvement of PARP, a marginal role of ROS and a pro-apoptotic role of Akt in this system, and raise attention to a novel mechanism that should be considered when cancer therapy is augmented with PARP-inhibition, namely the cytoprotection by inhibition of JNK2.

KW - c-Jun N-terminal kinase (JNK)

KW - Mitochondrial depolarization

KW - Mitogen activated protein kinase (MAPK)

KW - Poly(ADP-ribose)-polymerase (PARP)

KW - Protein kinase B (PKB/Akt)

UR - http://www.scopus.com/inward/record.url?scp=84860819343&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860819343&partnerID=8YFLogxK

U2 - 10.1186/1476-4598-11-34

DO - 10.1186/1476-4598-11-34

M3 - Article

VL - 11

JO - Molecular Cancer

JF - Molecular Cancer

SN - 1476-4598

M1 - 34

ER -