Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines

Andrea Sau, Giuseppe Filomeni, Silvia Pezzola, Simona D'Aguanno, Francesca Pellizzari Tregno, Andrea Urbani, Massimo Serra, Michela Pasello, Piero Picci, Giorgio Federici, Anna Maria Caccuri

Research output: Contribution to journalArticle

Abstract

The effect of the glutathione transferase P1-1 (GSTP1-1) targeting has been investigated in both sensitive (U-2OS) and cisplatin-resistant (U-2OS/CDDP4 μg) human osteosarcoma cell lines. Despite the different enzyme's content, inhibition of GSTP1-1 by 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) causes the activation of c-Jun N-terminal kinase (JNK) and apoptosis in both cell lines. However, different time courses of JNK activation and cell responses are observed. Whereas in the U-2OS/CDDP4 μg cell line drug treatment results in an early increase of caspase activity and secondary necrosis, in the U-2OS cells it mainly causes an early cell cycle arrest followed by apoptosis. In order to elucidate the action mechanism of NBDHEX we performed a proteomic investigation by label-free nLC-MS E. The high-throughput analysis associated with a bioinformatic tool suggested the involvement of the TNF receptor associated factor (TRAF) family in the cellular response to the drug treatment. We report experimental evidence of the interaction between GSTP1-1 and TRAF2 and we demonstrate that NBDHEX is able to dissociate the GSTP1-1:TRAF2 complex. This restores the TRAF2:ASK1 signaling, thereby leading to the simultaneous and prolonged activation of JNK and p38. These mitogen-activated protein kinases (MAPKs) mediate different effects: JNK is crucial for apoptosis, whereas p38 causes an increase in the p21 level and a concomitant cell cycle arrest. Our study shows that GSTP1-1 plays an important regulatory role in TRAF signaling of osteosarcoma and discloses new features of the action mechanism of NBDHEX that suggest potentially practical consequences of these findings.

Original languageEnglish
Pages (from-to)994-1006
Number of pages13
JournalMolecular BioSystems
Volume8
Issue number4
DOIs
Publication statusPublished - Mar 2012

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TNF Receptor-Associated Factor 2
Hexanols
Osteosarcoma
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Cisplatin
Phosphotransferases
Apoptosis
Cell Cycle Checkpoints
Cell Line
Glutathione S-Transferase pi
JNK Mitogen-Activated Protein Kinases
Caspases
Mitogen-Activated Protein Kinases
Computational Biology
Pharmaceutical Preparations
Proteomics
Necrosis
Enzymes

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Biology

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Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines. / Sau, Andrea; Filomeni, Giuseppe; Pezzola, Silvia; D'Aguanno, Simona; Tregno, Francesca Pellizzari; Urbani, Andrea; Serra, Massimo; Pasello, Michela; Picci, Piero; Federici, Giorgio; Caccuri, Anna Maria.

In: Molecular BioSystems, Vol. 8, No. 4, 03.2012, p. 994-1006.

Research output: Contribution to journalArticle

Sau, Andrea ; Filomeni, Giuseppe ; Pezzola, Silvia ; D'Aguanno, Simona ; Tregno, Francesca Pellizzari ; Urbani, Andrea ; Serra, Massimo ; Pasello, Michela ; Picci, Piero ; Federici, Giorgio ; Caccuri, Anna Maria. / Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines. In: Molecular BioSystems. 2012 ; Vol. 8, No. 4. pp. 994-1006.
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AU - Sau, Andrea

AU - Filomeni, Giuseppe

AU - Pezzola, Silvia

AU - D'Aguanno, Simona

AU - Tregno, Francesca Pellizzari

AU - Urbani, Andrea

AU - Serra, Massimo

AU - Pasello, Michela

AU - Picci, Piero

AU - Federici, Giorgio

AU - Caccuri, Anna Maria

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