The effect of the glutathione transferase P1-1 (GSTP1-1) targeting has been investigated in both sensitive (U-2OS) and cisplatin-resistant (U-2OS/CDDP4μg) 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/CDDP4μg cell line drug treatment results in an early increase of caspase activity and secondary necrosis, in the U-2OS cells it mainly causes cell cycle arrest followed by apoptosis. Thereafter, we detailed the action mechanism of NBDHEX in the U-2OS cell line. We report evidence of the interaction between GSTP1-1 and the TNF receptor associated factor 2 (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 finding.

Sau, A., Filomeni, G., Pezzola, S., D'Aguanno, S., Tregno, F., Urbani, A., et al. (2012). Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines. MOLECULAR BIOSYSTEMS, 8(4), 994-1006 [10.1039/c1mb05295k].

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

FILOMENI, GIUSEPPE;URBANI, ANDREA;FEDERICI, GIORGIO;CACCURI, ANNA MARIA
2012-04-01

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/CDDP4μg) 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/CDDP4μg cell line drug treatment results in an early increase of caspase activity and secondary necrosis, in the U-2OS cells it mainly causes cell cycle arrest followed by apoptosis. Thereafter, we detailed the action mechanism of NBDHEX in the U-2OS cell line. We report evidence of the interaction between GSTP1-1 and the TNF receptor associated factor 2 (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 finding.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10
English
Con Impact Factor ISI
GSTP1-1; JNK; MAPK; NBDHEX; osteosarcoma; TRAF2
Sau, A., Filomeni, G., Pezzola, S., D'Aguanno, S., Tregno, F., Urbani, A., et al. (2012). Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines. MOLECULAR BIOSYSTEMS, 8(4), 994-1006 [10.1039/c1mb05295k].
Sau, A; Filomeni, G; Pezzola, S; D'Aguanno, S; Tregno, F; Urbani, A; Serra, M; Pasello, M; Picci, P; Federici, G; Caccuri, Am
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/65069
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