PARP1 inhibition affects pleural mesothelioma cell viability and uncouples AKT/mTOR axis via SIRT1.
J Cell Mol Med
; 17(2): 233-41, 2013 Feb.
Article
em En
| MEDLINE
| ID: mdl-23301673
ABSTRACT
Malignant Pleural Mesothelioma (MMe) is a rare but increasingly prevalent, highly aggressive cancer with poor prognosis. The aetiology of MMe is essentially a function of previous exposure to asbestos fibres, which are considered to be an early-stage carcinogen. Asbestos is toxic to human mesothelial cells (HMCs), that activate the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP1) to repair DNA. The targeting of PARP1 is showing considerable potential for delivering selective tumour cell kill while sparing normal cells, and offers a scientifically rational clinical application. We investigated PARP1 expression in normal mesothelial and MMe tissues samples. Immunohistochemical analysis revealed low PARP1 staining in peritumoural mesothelium. As opposite, a progressive increase in epithelioid and in the most aggressive sarcomatoid MMe tissues was evident. In MMe cell lines, we correlated increased PARP1 expression to sensitivity to its inhibitor CO-338 and demonstrated that CO-338 significantly reduced cell viability as single agent and was synergistic with cis-platin. Interestingly, we described a new correlation between PARP1 and the AKT/mTOR axis regulated by SIRT1. SIRT1 has a role in the modulation of AKT activation and PARP1 has been described to be a gatekeeper for SIRT1 activity by limiting NAD+ availability. Here, we firstly demonstrate an inverse correlation between AKT acetylation and phosphorylation modulated by SIRT1 in MMe cells treated with CO-338. In conclusion, this study demonstrates that PARP1 overexpression defines increased responsiveness to its inhibition, then these results imply that a substantial fraction of patients could be candidates for therapy with PARP inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Apoptose
/
Proliferação de Células
/
Proteínas Proto-Oncogênicas c-akt
/
Sirtuína 1
/
Serina-Treonina Quinases TOR
/
Inibidores de Poli(ADP-Ribose) Polimerases
/
Mesotelioma
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Aged
/
Aged80
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
J Cell Mol Med
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Itália