APE-1/Ref-1 Inhibition Blocks Malignant Pleural Mesothelioma Cell Proliferation and Migration: Crosstalk between Oxidative Stress and Epithelial Mesenchymal Transition (EMT) in Driving Carcinogenesis and Metastasis

Our plain-English summary of APE-1/Ref-1 Inhibition Blocks Malignant Pleural Mesothelioma Cell Proliferation and Migration: Crosstalk between Oxidative Stress and Epithelial Mesenchymal Transition (EMT) in Driving Carcinogenesis and Metastasis, by V. Ramundo, G. Zanirato, M.L. Palazzo, et al (International Journal of Molecular Sciences, 2023).

The study

• Authors: V. Ramundo, G. Zanirato, M.L. Palazzo, C. Riganti, E. Aldieri
• Journal: International Journal of Molecular Sciences
• Published: 2023;24(16)
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with asbestos exposure. MPM pathogenesis has been related both to oxidative stress, evoked by and in response to asbestos fibers exposure, and epithelial mesenchymal transition (EMT), an event induced by oxidative stress itself and related to cancer proliferation and metastasis. Asbestos-related primary oxidative damage is counteracted in the lungs by various redox-sensitive factors, often hyperactivated in some cancers. Among these redox-sensitive factors, Apurinic-apyrimidinic endonuclease 1 (APE-1)/Redox effector factor 1 (Ref-1) has been demonstrated to be overexpressed in MPM and lung cancer, but the molecular mechanism has not yet been fully understood. Moreover, asbestos exposure has been associated with induced EMT events, via some EMT transcription factors, such as Twist, Zeb-1 and Snail-1, in possible crosstalk with oxidative stress and inflammation events. To demonstrate this hypothesis, we inhibited/silenced Ref-1 in MPM cells; as a consequence, both EMT (Twist, Zeb-1 and Snail-1) markers and cellular migration/proliferation were significantly inhibited. Taken as a whole, these results show, for the first time, crosstalk between oxidative stress and EMT in MPM carcinogenesis and invasiveness, thus improving the knowledge to better address a preventive and therapeutic approach against this aggressive cancer.

In plain English

This laboratory study used human cells grown in dishes. The cells were not exposed to asbestos in these experiments. The authors used mesothelioma cells (MSTO-211H, described as biphasic mesothelioma), lung adenocarcinoma cells (A549) and human mesothelial cells (Met-5A). They studied Ref-1 (also called APE-1), a protein involved in DNA repair and in responses to oxidative stress. Ref-1 levels were significantly higher in the mesothelioma cells than in the mesothelial cells. The authors lowered Ref-1 either with a drug inhibitor, E3330, or by silencing the gene (siRNA). With E3330, only Twist fell significantly; Twist is one of three proteins linked to epithelial mesenchymal transition (EMT). The other two, Zeb-1 and Snail-1, fell partially but not significantly. With silencing, all three fell significantly in the mesothelioma cells. After 24 hours, silencing reduced cell migration by 31% in the mesothelioma cells and by 81% in the lung cancer cells. It also lowered a growth marker, PCNA, in both. The authors concluded that Ref-1 could be a promising marker and treatment target in pleural mesothelioma. They noted that many points about the mechanism remain to be clarified.

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 (in vitro) experiments on human cell lines
• Who was studied: Three commercially obtained human cell lines: MSTO-211H (human biphasic mesothelioma cells), A549 (human lung adenocarcinoma, used as a positive control for Ref-1 overexpression in cancer) and Met-5A (human mesothelial cells); no human subjects
• Exposure: No asbestos was used in the experiments. Cells were treated for 48 hours with the Ref-1 inhibitor E3330 at 20, 30 or 50 micromoles per litre, or were transfected for 48 hours with 60 nM Ref-1-targeted siRNA to silence Ref-1
• Main results:
  • Ref-1 was significantly overexpressed in MSTO-211H mesothelioma cells compared with Met-5A mesothelial cells
  • E3330 significantly decreased Ref-1 levels in both MSTO-211H and A549 cells, particularly at the highest dose of 50 µM
  • Ref-1 siRNA significantly decreased Ref-1 levels in both MSTO-211H and A549 cells
  • In MSTO-211H cells treated with 50 µM E3330, only Twist was significantly reduced; Zeb-1 and Snail-1 were partially but not significantly reduced
  • After Ref-1 silencing, Twist, Zeb-1 and Snail-1 were all significantly decreased in MSTO-211H cells
  • In a scratch assay, Ref-1 silencing significantly reduced the migration rate after 24 hours by 31% in MSTO-211H cells and by 81% in A549 cells
  • Ref-1 silencing strongly reduced the proliferation marker PCNA in both MSTO-211H and A549 cells
  • In MSTO-211H cells, an MTT assay showed significantly reduced cell survival after Ref-1 silencing (reported in supplementary materials)
• The authors' conclusion: The authors concluded that Ref-1 can be considered a promising predictive/prognostic marker and therapeutic target in malignant pleural mesothelioma. They also stated that their results showed crosstalk between oxidative stress and EMT.
• Limitations the authors state:
  • The authors noted that many points about the molecular mechanism remain to be clarified

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, Oxidative Stress, Carcinogenesis, Metastasis, Asbestos Exposure, Lung Cancer, Inflammation.

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