We previously demonstrated that the complex bis[(2-oxindol-3-ylimino)-2-(2-aminoethyl)pyridine-N,N']copper(II), named [Cu(isaepy)2], induces AMPK-dependent/p53-mediated apoptosis in tumour cells by targeting mitochondria. Here, we reveal that p38MAPK is the molecular link of the phosphorylative cascade connecting AMPK to p53. Transfection of SH-SY5Y with a dominant negative mutant of AMPK results in apoptosis decrease, and a significant reduction of phospho-active p38MAPK and p53. Similarly, reverse genetics of p38MAPK yields a reduction of p53 and decreases apoptotic extent, confirming an exclusive hierarchy of activation that proceeds via AMPK/p38MAPK/p53. Fuel supplies counteract [Cu(isaepy)2]-induced apoptosis and AMPK/p38MAPK/p53 activation, with glucose being the most effective, suggesting a role for energetic dysbalance in [Cu(isaepy)2] toxicity. Co-administration of 3-bromopyruvate (3BrPA), a well-known inhibitor of glycolysis and succinate dehydrogenase, enhances apoptosis and AMPK/p38MAPK/p53 signalling pathway activation. Under these conditions, no toxic effect is observed in superoxide dismutase-overexpressing SH-SY5Y, or in primary cortical neurons (PCN), which are, conversely sensitized to the combined treatment with [Cu(isaepy)2] and 3BrPA only if grown in low glucose, or incubated with the glucose-6-phosphate dehydrogenase inhibitor, dehyroepiandrosterone. Overall, the results suggest that NADPH deriving from pentose phosphate pathway contributes to PCN resistance against [Cu(isaepy)2] toxicity and propose its employment in combination with 3BrPA as possible tool for cancer treatment.

Filomeni, G., Cardaci, S., Da Costa Ferreira, A., Rotilio, G., Ciriolo, M.r. (2011). Metabolic oxidative stress elicited by the copper(II) complex [Cu(isaepy)2] triggers apoptosis in SH-SY5Y cells through the induction of AMP-activated protein kinase/p38MAPK/p53 signalling axis Evidence for a combined use with 3-bromopyruvate in neuroblastoma treatment. BIOCHEMICAL JOURNAL, 437(3), 443-453 [10.1042/BJ20110510].

Metabolic oxidative stress elicited by the copper(II) complex [Cu(isaepy)2] triggers apoptosis in SH-SY5Y cells through the induction of AMP-activated protein kinase/p38MAPK/p53 signalling axis Evidence for a combined use with 3-bromopyruvate in neuroblastoma treatment

FILOMENI, GIUSEPPE;ROTILIO, GIUSEPPE;CIRIOLO, MARIA ROSA
2011-05-06

Abstract

We previously demonstrated that the complex bis[(2-oxindol-3-ylimino)-2-(2-aminoethyl)pyridine-N,N']copper(II), named [Cu(isaepy)2], induces AMPK-dependent/p53-mediated apoptosis in tumour cells by targeting mitochondria. Here, we reveal that p38MAPK is the molecular link of the phosphorylative cascade connecting AMPK to p53. Transfection of SH-SY5Y with a dominant negative mutant of AMPK results in apoptosis decrease, and a significant reduction of phospho-active p38MAPK and p53. Similarly, reverse genetics of p38MAPK yields a reduction of p53 and decreases apoptotic extent, confirming an exclusive hierarchy of activation that proceeds via AMPK/p38MAPK/p53. Fuel supplies counteract [Cu(isaepy)2]-induced apoptosis and AMPK/p38MAPK/p53 activation, with glucose being the most effective, suggesting a role for energetic dysbalance in [Cu(isaepy)2] toxicity. Co-administration of 3-bromopyruvate (3BrPA), a well-known inhibitor of glycolysis and succinate dehydrogenase, enhances apoptosis and AMPK/p38MAPK/p53 signalling pathway activation. Under these conditions, no toxic effect is observed in superoxide dismutase-overexpressing SH-SY5Y, or in primary cortical neurons (PCN), which are, conversely sensitized to the combined treatment with [Cu(isaepy)2] and 3BrPA only if grown in low glucose, or incubated with the glucose-6-phosphate dehydrogenase inhibitor, dehyroepiandrosterone. Overall, the results suggest that NADPH deriving from pentose phosphate pathway contributes to PCN resistance against [Cu(isaepy)2] toxicity and propose its employment in combination with 3BrPA as possible tool for cancer treatment.
6-mag-2011
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10 - BIOCHIMICA
English
Con Impact Factor ISI
AMP-Activated Protein Kinase; Apoptosis; Neuroblastoma; Oxidative Stress; Tumor Suppressor Protein p53; metabolism; p38 Mitogen-Activated Protein Kinase
Filomeni, G., Cardaci, S., Da Costa Ferreira, A., Rotilio, G., Ciriolo, M.r. (2011). Metabolic oxidative stress elicited by the copper(II) complex [Cu(isaepy)2] triggers apoptosis in SH-SY5Y cells through the induction of AMP-activated protein kinase/p38MAPK/p53 signalling axis Evidence for a combined use with 3-bromopyruvate in neuroblastoma treatment. BIOCHEMICAL JOURNAL, 437(3), 443-453 [10.1042/BJ20110510].
Filomeni, G; Cardaci, S; Da Costa Ferreira, A; Rotilio, G; Ciriolo, Mr
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
BJ 2011.pdf

accesso aperto

Dimensione 1 MB
Formato Unknown
1 MB Unknown Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/14119
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 35
  • ???jsp.display-item.citation.isi??? 35
social impact