Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance

Mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

W. Bunjobpol, I. Dulloo, K. Igarashi, N. Concin, Koichi Matsuo, K. Sabapathy

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Enhanced resistance to chemotherapy has been correlated with high levels of Delta-Np73 (DNp73), an anti-apoptotic protein of the p53 tumor-suppressor family which inhibits the pro-apoptotic members such as p53 and TAp73. Although genotoxic drugs have been shown to induce DNp73 degradation, lack of mechanistic understanding of this process precludes strategies to enhance the targeting of DNp73 and improve treatment outcomes. Antizyme (Az) is a mediator of ubiquitin-independent protein degradation regulated by the polyamine biosynthesis pathway. We show here that acetylpolyamine oxidase (PAOX), a catabolic enzyme of this pathway, upregulates DNp73 levels by suppressing its degradation via the Az pathway. Conversely, downregulation of PAOX activity by siRNA-mediated knockdown or chemical inhibition leads to DNp73 degradation in an Az-dependent manner. PAOX expression is suppressed by several genotoxic drugs, via selected members of the activator protein-1 (AP-1) transcription factors, namely c-Jun, JunB and FosB, which are required for stress-mediated DNp73 degradation. Finally, chemical- and siRNA-mediated inhibition of PAOX significantly reversed the resistant phenotype of DNp73-overexpressing cancer cells to genotoxic drugs. Together, these data define a critical mechanism for the regulation of DNp73 abundance, and reveal that inhibition of PAOX could widen the therapeutic index of cytotoxic drugs and overcome DNp73-mediated chemoresistance in tumors.

Original languageEnglish
Pages (from-to)1240-1249
Number of pages10
JournalCell Death and Differentiation
Volume21
Issue number8
DOIs
Publication statusPublished - 2014

Fingerprint

Transcription Factor AP-1
Oxidoreductases
Pharmaceutical Preparations
Small Interfering RNA
Neoplasms
Apoptosis Regulatory Proteins
Polyamines
Ubiquitin
Proteolysis
Transcription Factors
Up-Regulation
Down-Regulation
Phenotype
Drug Therapy
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance : Mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs. / Bunjobpol, W.; Dulloo, I.; Igarashi, K.; Concin, N.; Matsuo, Koichi; Sabapathy, K.

In: Cell Death and Differentiation, Vol. 21, No. 8, 2014, p. 1240-1249.

Research output: Contribution to journalArticle

@article{36204553a9c44fabb0fadd3363b12bbf,
title = "Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: Mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs",
abstract = "Enhanced resistance to chemotherapy has been correlated with high levels of Delta-Np73 (DNp73), an anti-apoptotic protein of the p53 tumor-suppressor family which inhibits the pro-apoptotic members such as p53 and TAp73. Although genotoxic drugs have been shown to induce DNp73 degradation, lack of mechanistic understanding of this process precludes strategies to enhance the targeting of DNp73 and improve treatment outcomes. Antizyme (Az) is a mediator of ubiquitin-independent protein degradation regulated by the polyamine biosynthesis pathway. We show here that acetylpolyamine oxidase (PAOX), a catabolic enzyme of this pathway, upregulates DNp73 levels by suppressing its degradation via the Az pathway. Conversely, downregulation of PAOX activity by siRNA-mediated knockdown or chemical inhibition leads to DNp73 degradation in an Az-dependent manner. PAOX expression is suppressed by several genotoxic drugs, via selected members of the activator protein-1 (AP-1) transcription factors, namely c-Jun, JunB and FosB, which are required for stress-mediated DNp73 degradation. Finally, chemical- and siRNA-mediated inhibition of PAOX significantly reversed the resistant phenotype of DNp73-overexpressing cancer cells to genotoxic drugs. Together, these data define a critical mechanism for the regulation of DNp73 abundance, and reveal that inhibition of PAOX could widen the therapeutic index of cytotoxic drugs and overcome DNp73-mediated chemoresistance in tumors.",
author = "W. Bunjobpol and I. Dulloo and K. Igarashi and N. Concin and Koichi Matsuo and K. Sabapathy",
year = "2014",
doi = "10.1038/cdd.2014.41",
language = "English",
volume = "21",
pages = "1240--1249",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance

T2 - Mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

AU - Bunjobpol, W.

AU - Dulloo, I.

AU - Igarashi, K.

AU - Concin, N.

AU - Matsuo, Koichi

AU - Sabapathy, K.

PY - 2014

Y1 - 2014

N2 - Enhanced resistance to chemotherapy has been correlated with high levels of Delta-Np73 (DNp73), an anti-apoptotic protein of the p53 tumor-suppressor family which inhibits the pro-apoptotic members such as p53 and TAp73. Although genotoxic drugs have been shown to induce DNp73 degradation, lack of mechanistic understanding of this process precludes strategies to enhance the targeting of DNp73 and improve treatment outcomes. Antizyme (Az) is a mediator of ubiquitin-independent protein degradation regulated by the polyamine biosynthesis pathway. We show here that acetylpolyamine oxidase (PAOX), a catabolic enzyme of this pathway, upregulates DNp73 levels by suppressing its degradation via the Az pathway. Conversely, downregulation of PAOX activity by siRNA-mediated knockdown or chemical inhibition leads to DNp73 degradation in an Az-dependent manner. PAOX expression is suppressed by several genotoxic drugs, via selected members of the activator protein-1 (AP-1) transcription factors, namely c-Jun, JunB and FosB, which are required for stress-mediated DNp73 degradation. Finally, chemical- and siRNA-mediated inhibition of PAOX significantly reversed the resistant phenotype of DNp73-overexpressing cancer cells to genotoxic drugs. Together, these data define a critical mechanism for the regulation of DNp73 abundance, and reveal that inhibition of PAOX could widen the therapeutic index of cytotoxic drugs and overcome DNp73-mediated chemoresistance in tumors.

AB - Enhanced resistance to chemotherapy has been correlated with high levels of Delta-Np73 (DNp73), an anti-apoptotic protein of the p53 tumor-suppressor family which inhibits the pro-apoptotic members such as p53 and TAp73. Although genotoxic drugs have been shown to induce DNp73 degradation, lack of mechanistic understanding of this process precludes strategies to enhance the targeting of DNp73 and improve treatment outcomes. Antizyme (Az) is a mediator of ubiquitin-independent protein degradation regulated by the polyamine biosynthesis pathway. We show here that acetylpolyamine oxidase (PAOX), a catabolic enzyme of this pathway, upregulates DNp73 levels by suppressing its degradation via the Az pathway. Conversely, downregulation of PAOX activity by siRNA-mediated knockdown or chemical inhibition leads to DNp73 degradation in an Az-dependent manner. PAOX expression is suppressed by several genotoxic drugs, via selected members of the activator protein-1 (AP-1) transcription factors, namely c-Jun, JunB and FosB, which are required for stress-mediated DNp73 degradation. Finally, chemical- and siRNA-mediated inhibition of PAOX significantly reversed the resistant phenotype of DNp73-overexpressing cancer cells to genotoxic drugs. Together, these data define a critical mechanism for the regulation of DNp73 abundance, and reveal that inhibition of PAOX could widen the therapeutic index of cytotoxic drugs and overcome DNp73-mediated chemoresistance in tumors.

UR - http://www.scopus.com/inward/record.url?scp=84905039245&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905039245&partnerID=8YFLogxK

U2 - 10.1038/cdd.2014.41

DO - 10.1038/cdd.2014.41

M3 - Article

VL - 21

SP - 1240

EP - 1249

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

IS - 8

ER -