2-Methoxyestradiol Affects Mitochondrial Biogenesis Pathway and Succinate Dehydrogenase Complex Flavoprotein Subunit A in Osteosarcoma Cancer Cells
| Autor: | Stephan Nussberger, Alicja Kuban-Jankowska, Giosuè Lo Bosco, Giampaolo Barone, Stephan A. Eisler, Ugo Perricone, Magdalena Gorska-Ponikowska |
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| Přispěvatelé: | Gorska-Ponikowska, M., Kuban-Jankowska, A., Eisler, S., Perricone, U., Lo Bosco, G., Barone, G., Nussberger, S. |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research SIRT3 Protein subunit SDHA Muscle Proteins Antineoplastic Agents Molecular Dynamics Simulation Biochemistry Electron Transport Complex IV 03 medical and health sciences 0302 clinical medicine Genetic Settore BIO/10 - Biochimica Cell Line Tumor Sirtuin 3 Coactivator Genetics Humans Molecular Biology Osteosarcoma Organelle Biogenesis biology Estradiol Settore BIO/16 - Anatomia Umana Chemistry Electron Transport Complex II Calcium-Binding Proteins Membrane Proteins Peroxisome Mitochondrial biogenesi Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Cell biology 2-Methoxyestradiol Mitochondria Succinate dehydrogenase Molecular Docking Simulation 030104 developmental biology Mitochondrial biogenesis Settore CHIM/03 - Chimica Generale E Inorganica 030220 oncology & carcinogenesis Sirtuin Cancer cell biology.protein Research Article |
| Zdroj: | Cancer genomicsproteomics. 15(1) |
| ISSN: | 1790-6245 |
| Popis: | Background/aim Dysregulation of mitochondrial pathways is implicated in several diseases, including cancer. Notably, mitochondrial respiration and mitochondrial biogenesis are favored in some invasive cancer cells, such as osteosarcoma. Hence, the aim of the current work was to investigate the effects of 2-methoxyestradiol (2-ME), a potent anticancer agent, on the mitochondrial biogenesis of osteosarcoma cells. Materials and methods Highly metastatic osteosarcoma 143B cells were treated with 2-ME separately or in combination with L-lactate, or with the solvent (non-treated control cells). Protein levels of α-syntrophin and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) were determined by western blotting. Impact of 2-ME on mitochondrial mass, regulation of cytochrome c oxidase I (COXI) expression, and succinate dehydrogenase complex flavoprotein subunit A (SDHA) was determined by immunofluorescence analyses. Inhibition of sirtuin 3 (SIRT3) activity by 2-ME was investigated by fluorescence assay and also, using molecular docking and molecular dynamics simulations. Results L-lactate induced mitochondrial biogenesis pathway via up-regulation of COXI. 2-ME inhibited mitochondrial biogenesis via regulation of PGC-1α, COXI, and SIRT3 in a concentration-dependent manner as a consequence of nuclear recruitment of neuronal nitric oxide synthase and nitric oxide generation. It was also proved that 2-ME inhibited SIRT3 activity by binding to both the canonical and allosteric inhibitor binding sites. Moreover, regardless of the mitochondrial biogenesis pathway, 2-ME affected the expression of SDHA. Conclusion Herein, mitochondrial biogenesis pathway regulation and SDHA were presented as novel targets of 2-ME, and moreover, 2-ME was demonstrated as a potent inhibitor of SIRT3. L-lactate was confirmed to exert pro-carcinogenic effects on osteosarcoma cells via the induction of the mitochondrial biogenesis pathway. Thus, L-lactate level may be considered as a prognostic biomarker for osteosarcoma. |
| Databáze: | OpenAIRE |
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