Targeting Human Lung Adenocarcinoma with a Suppressor of Mitochondrial Superoxide Production
| Autor: | Laetitia Dard, Hamid Reza Rezvani, Didier Lacombe, Walid Mahfouf, Rodrigue Rossignol, Saharnaz Sarlak, Wendy Blanchard, Ciro Leonardo Pierri, Julien Izotte, Nivea Dias Amoedo, Benoit Rousseau, Stéphane Claverol |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Physiology Clinical Biochemistry Adenocarcinoma of Lung Mitochondrion Biochemistry Cyclic N-Oxides 03 medical and health sciences medicine Humans Mode of action Molecular Biology General Environmental Science chemistry.chemical_classification Reactive oxygen species Electron Transport Complex I 030102 biochemistry & molecular biology Chemistry Cancer Cell Biology medicine.disease Warburg effect Mitochondria 030104 developmental biology Proteome Cancer research General Earth and Planetary Sciences Adenocarcinoma Reactive Oxygen Species Oxidation-Reduction Reprogramming Signal Transduction |
| Zdroj: | Antioxidants & Redox Signaling. 33:883-902 |
| ISSN: | 1557-7716 1523-0864 |
| Popis: | Aims: REDOX signaling from reactive oxygen species (ROS) generated by the mitochondria (mitochondrial reactive oxygen species [mtROS]) has been implicated in cancer growth and survival. Here, we investigated the effect of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (AOL), a recently characterized member of the new class of mtROS suppressors (S1QELs), on human lung adenocarcinoma proteome reprogramming, bioenergetics, and growth. Results: AOL reduced steady-state cellular ROS levels in human lung cancer cells without altering the catalytic activity of complex I. AOL treatment induced dose-dependent inhibition of lung cancer cell proliferation and triggered a reduction in tumor growth in vivo. Molecular investigations demonstrated that AOL reprogrammed the proteome of human lung cancer cells. In particular, AOL suppressed the determinants of the Warburg effect and increased the expression of the complex I subunit NDUFV1 which was also identified as AOL binding site using molecular modeling computer simulations. Comparison of the molecular changes induced by AOL and MitoTEMPO, an mtROS scavenger that is not an S1QEL, identified a core component of 217 proteins commonly altered by the two treatments, as well as drug-specific targets. Innovation: This study provides proof-of-concept data on the anticancer effect of AOL on mouse orthotopic human lung tumors. A unique dataset on proteomic reprogramming by AOL and MitoTEMPO is also provided. Lastly, our study revealed the repression of NDUFV1 by S1QEL AOL. Conclusion: Our findings demonstrate the preclinical anticancer properties of S1QEL AOL and delineate its mode of action on REDOX and cancer signaling. |
| Databáze: | OpenAIRE |
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