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

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.

Poly(ADP-ribose) polymerases as modulators of mitochondrial activity

“…PARP inhibition by structurally different PARP inhibitors increases the activity of PI3K [35] and Akt [34][35][36] thus preventing the loss of the mitochondrial membrane potential upon oxidative damage [34]. Tankyrases are also likely to possess regulatory properties over mitochondria by interacting with GSK3 [37].…”

Nobiletin induces growth inhibition and apoptosis in human nasopharyngeal carcinoma C666‐1 cells through regulating PARP‐2/SIRT1/AMPK signaling pathway

“…PARP-1 and PARP-2 regulate SIRT1 via different mechanisms. PARP-1 increase SIRT1 activity indirectly through the modulation of NAD + levels (Pinton et al, 2013). Instead, PARP-2 is found to bind directly to the SIRT1 proximal promoter where it acts to negatively regulate SIRT1 expression (Chung & Joe, 2014).…”

The Role and Application of Sirtuins and mTOR Signaling in the Control of Ovarian Functions

“…SIRTs affect these processes via the down-regulation of a serine/threonine kinase called mammalian target of rapamycin (mTOR) [8,9] and other intracellular signaling pathways [5], although mTOR can in turn up-regulate SIRTs production [9,10,11,12]. Recently, SIRTs and their regulators have been intensively studied to examine the potential of SIRTs to be diagnostic and predictive indexes for some disorders, and to be useful for the treatment of malignant and metabolic disorders.…”