Metabolic rewiring and redox alterations in malignant pleural mesothelioma

Urso, Loredana; Cavallari, Ilaria; Sharova, Evgeniya; Ciccarese, Francesco; Pasello, Giulia; Ciminale, Vincenzo

doi:10.1038/s41416-019-0661-9

Cited by 25 publications

(28 citation statements)

References 122 publications

(176 reference statements)

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“…In the contest of MPM, it has been demonstrated that the PI3K/AKT/mTOR pathway is frequently up-regulated probably because of the high release of reactive oxygen species (ROS) resulting from asbestos exposure. Indeed, ROS can directly lead to the inactivation of PTEN, a lipid phosphatase involved in the negative regulation of this pathway, through the oxidation of its cysteine residues [20]. Recently, loss of PTEN expression has been reported in a high percentage of human sarcomatoid MPM as compared with other subtypes [15].…”

Section: Discussionmentioning

confidence: 99%

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Bonelli

Terenziani

Zoppi

et al. 2020

IJMS

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Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination.

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Section: Discussionmentioning

confidence: 99%

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Bonelli

Terenziani

Zoppi

et al. 2020

IJMS

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“…As a class I carcinogenic heavy metal, arsenic can increase ROS levels via Fenton reaction, thus participating in the progressions of multiple malignancies 13 , 14 . Inhaled asbestos fibers accumulate in lungs and induce the generation of ROS due to the presence of iron associated with the fibrous silicates, which promote the malignant transformation of mesothelial cells 15 . Ultraviolet radiation (UVR) increases oxidative stress not only by upregulating nitric oxide synthase (NOS) synthesis but also by impeding catalase (CAT) to scavenge hydrogen peroxide, thus leading to increased risk of sunburn, photoaging and skin cancer 16 .…”

Section: Sources Of Rosmentioning

confidence: 99%

The double-edged roles of ROS in cancer prevention and therapy

et al. 2021

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Reactive oxygen species (ROS) serve as cell signaling molecules generated in oxidative metabolism and are associated with a number of human diseases. The reprogramming of redox metabolism induces abnormal accumulation of ROS in cancer cells. It has been widely accepted that ROS play opposite roles in tumor growth, metastasis and apoptosis according to their different distributions, concentrations and durations in specific subcellular structures. These double-edged roles in cancer progression include the ROS-dependent malignant transformation and the oxidative stress-induced cell death. In this review, we summarize the notable literatures on ROS generation and scavenging, and discuss the related signal transduction networks and corresponding anticancer therapies. There is no doubt that an improved understanding of the sophisticated mechanism of redox biology is imperative to conquer cancer.

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“…The PI3K/Akt signaling pathway is involved in cell survival and its activity can be redox-regulated. This point is particularly relevant in MPM, since it is well known that asbestos toxicity is mainly related to the release of ROS [ 74 , 75 ]. The analysis of transcriptomes and whole exomes confirmed that the PI3K/mTor pathways are activated in MPM [ 76 ].…”

Section: Germline and Somatic Changesmentioning

confidence: 99%

The Evolving Landscape of the Molecular Epidemiology of Malignant Pleural Mesothelioma

Lettieri

Bortolotto

Agustoni

et al. 2021

JCM

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Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural lining of the lungs. It has a strong association with exposure to biopersistent fibers, mainly asbestos (80% of cases) and—in specific geographic regions—erionite, zeolites, ophiolites, and fluoro-edenite. Individuals with a chronic exposure to asbestos generally have a long latency with no or few symptoms. Then, when patients do become symptomatic, they present with advanced disease and a worse overall survival (about 13/15 months). The fibers from industrial production not only pose a substantial risk to workers, but also to their relatives and to the surrounding community. Modern targeted therapies that have shown benefit in other human tumors have thus far failed in MPM. Overall, MPM has been listed as orphan disease by the European Union. However, molecular high-throughput profiling is currently unveiling novel biomarkers and actionable targets. We here discuss the natural evolution, mainly focusing on the novel concept of molecular epidemiology. The application of innovative endpoints, quantification of genetic damages, and definition of genetic susceptibility are reviewed, with the ultimate goal to point out new tools for screening of exposed subject and for designing more efficient diagnostic and therapeutic strategies.

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Metabolic rewiring and redox alterations in malignant pleural mesothelioma

Cited by 25 publications

References 122 publications

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

The double-edged roles of ROS in cancer prevention and therapy

The Evolving Landscape of the Molecular Epidemiology of Malignant Pleural Mesothelioma

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