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

Our plain-English summary of PARP1 inhibition affects pleural mesothelioma cell viability and uncouples AKT/mTOR axis via SIRT1, by G. Pinton, A.G. Manente, B. Murer, et al (Journal of Cellular and Molecular Medicine, 2013).

The study

• Authors: G. Pinton, A.G. Manente, B. Murer, E. De Marino, L. Mutti, L. Moro
• Journal: Journal of Cellular and Molecular Medicine
• Published: 2013;17(2):233-41
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2012 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

In plain English

This laboratory study examined PARP1, a DNA-repair protein, in malignant pleural mesothelioma. It did not measure anyone's asbestos exposure. The authors stained tumour tissue from 70 patients (30 sarcomatoid, 10 biphasic and 30 epithelioid), along with the mesothelium surrounding each tumour. PARP1 staining was intense in all sarcomatoid samples and in the sarcomatoid part of the biphasic samples. It was progressively weaker in epithelioid tumours and in the surrounding mesothelium. In laboratory-grown cells, the PARP1-blocking drug CO-338 (rucaparib) reduced the viability of all three mesothelioma cell lines. Lines with more PARP1 were more sensitive, and normal mesothelial cells responded poorly. After 24 hours, the concentration that halved cell viability was 37, 16 and 14 micromolar for the epithelioid, biphasic and sarcomatoid lines. The drug stopped cells at one stage of the division cycle and changed signalling involving the proteins AKT, mTOR and SIRT1. Combined with the chemotherapy drug cisplatin, it killed cells strongly synergistically. The authors concluded that higher PARP1 levels meant greater responsiveness to blocking it, and that many patients could be candidates for PARP inhibitor therapy.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: immunohistochemistry (protein staining) of patient mesothelioma tissue samples, plus experiments on cultured mesothelioma and mesothelial cell lines
• Who was studied: Tissue from 70 patients with malignant pleural mesothelioma (52 males, 18 females, median age at diagnosis 63 years; 30 sarcomatoid, 10 biphasic, 30 epithelioid), with the mesothelium surrounding each tumour. Also cell lines: REN (epithelioid), MSTO-211H (biphasic) and H2596 (sarcomatoid) mesothelioma cells, and human mesothelial cells (HMCs) from patients with congestive heart failure, immortalized in the laboratory. Where and when the patients were treated is not stated.
• Exposure: No asbestos exposure was studied. The cells were treated with the PARP1 inhibitor CO-338 (rucaparib), alone or together with the chemotherapy drug cisplatin. Some normal mesothelial cells were also treated with hydrogen peroxide.
• Main results:
  • In the patient tissue, intense nuclear PARP1 staining was seen in all sarcomatoid samples and in the sarcomatoid component of the biphasic samples. Staining was progressively reduced in epithelioid samples and in the surrounding mesothelium.
  • CO-338 reduced the viability of all mesothelioma cell lines in a dose-dependent way. Normal mesothelial cells (HMCs), which have low PARP1, were poorly responsive. The concentrations halving viability at 24 hours were 37, 16 and 14 micromolar for REN, MSTO-211H and H2596 cells respectively.
  • Normal mesothelial cells became more sensitive to CO-338 after treatment with hydrogen peroxide.
  • In the three mesothelioma cell lines, 24 hours of CO-338 caused cells to build up at the G2/M stage of the cell cycle (cell cycle arrest).
  • Blocking PARP1 increased AKT phosphorylation, made AKT de-acetylated and reduced mTOR phosphorylation. The authors examined a role for SIRT1 in this.
  • CO-338 combined with cisplatin showed strong synergistic toxicity in all mesothelioma cell lines across a broad range of concentrations.
• The authors' conclusion: The authors concluded that overexpression of PARP1 defines increased responsiveness to its inhibition, and that a substantial fraction of patients could be candidates for therapy with PARP inhibitors.
• Limitations the authors state:
  • The authors stated that further studies are needed to understand exactly how SIRT1 regulation works.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Mesothelial Cells, Mesothelium, Epithelioid, Sarcomatoid.

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