PARP1 inhibition affects pleural mesothelioma cell viability and uncouples AKT/mTOR axis via SIRT1

Giulia Pinton, Arcangela Gabriella Manente, Bruno Murer, Elvira De Marino, Luciano Mutti, Laura Moro

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)233-241
Number of pages9
JournalJournal of Cellular and Molecular Medicine
Volume17
Issue number2
DOIs
Publication statusPublished - Feb 2013

Keywords

  • AKT/mTOR axis
  • Malignant pleural mesothelioma
  • PARP1
  • PARP1 inhibitor
  • Therapeutic target

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