2-methoxyestradiol affects mitochondrial biogenesis pathway and succinate dehydrogenase complex flavoprotein subunit a in osteosarcoma cancer cells

Giosue' Lo Bosco, Giampaolo Barone, Giosuè Lo Bosco, Stephan Nussberger, Stephan A. Eisler, Alicja Kuban-Jankowska, Ugo Perricone, Magdalena Gorska-Ponikowska

Risultato della ricerca: Article

Abstract

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: Llactate induced mitochondrial biogenesis pathway via upregulation of COXI. 2-ME inhibited mitochondrial biogenesis via regulation of PGC-1�, 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.
LinguaEnglish
Pagine73-89
Number of pages17
RivistaCANCER GENOMICS & PROTEOMICS.
Volume15
Publication statusPublished - 2018

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Flavoproteins
Succinate Dehydrogenase
Organelle Biogenesis
Osteosarcoma
Sirtuin 3
Cells
Neoplasms
Lactic Acid
Oxidoreductases
2-methoxyestradiol
Nitric Oxide Synthase Type I
Biomarkers
Electron Transport Complex IV
Molecular Dynamics Simulation
Antineoplastic Agents
Fluorescent Antibody Technique
Molecular dynamics
Assays
Nitric Oxide
Respiration

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cancer Research
  • Genetics
  • Molecular Biology

Cita questo

2-methoxyestradiol affects mitochondrial biogenesis pathway and succinate dehydrogenase complex flavoprotein subunit a in osteosarcoma cancer cells. / Lo Bosco, Giosue'; Barone, Giampaolo; Lo Bosco, Giosuè; Nussberger, Stephan; Eisler, Stephan A.; Kuban-Jankowska, Alicja; Perricone, Ugo; Gorska-Ponikowska, Magdalena.

In: CANCER GENOMICS & PROTEOMICS., Vol. 15, 2018, pag. 73-89.

Risultato della ricerca: Article

Lo Bosco, Giosue' ; Barone, Giampaolo ; Lo Bosco, Giosuè ; Nussberger, Stephan ; Eisler, Stephan A. ; Kuban-Jankowska, Alicja ; Perricone, Ugo ; Gorska-Ponikowska, Magdalena. / 2-methoxyestradiol affects mitochondrial biogenesis pathway and succinate dehydrogenase complex flavoprotein subunit a in osteosarcoma cancer cells. In: CANCER GENOMICS & PROTEOMICS. 2018 ; Vol. 15. pagg. 73-89.
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title = "2-methoxyestradiol affects mitochondrial biogenesis pathway and succinate dehydrogenase complex flavoprotein subunit a in osteosarcoma cancer cells",
abstract = "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 {\^I}±-syntrophin and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1{\^I}±) 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: Llactate induced mitochondrial biogenesis pathway via upregulation of COXI. 2-ME inhibited mitochondrial biogenesis via regulation of PGC-1{\"i}¿½, 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.",
keywords = "2-Methoxyestradiol; Mitochondrial biogenesis; Osteosarcoma; Sirtuin 3; Succinate dehydrogenase; Biochemistry; Molecular Biology; Genetics; Cancer Research",
author = "{Lo Bosco}, Giosue' and Giampaolo Barone and {Lo Bosco}, Giosu{\`e} and Stephan Nussberger and Eisler, {Stephan A.} and Alicja Kuban-Jankowska and Ugo Perricone and Magdalena Gorska-Ponikowska",
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pages = "73--89",
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TY - JOUR

T1 - 2-methoxyestradiol affects mitochondrial biogenesis pathway and succinate dehydrogenase complex flavoprotein subunit a in osteosarcoma cancer cells

AU - Lo Bosco, Giosue'

AU - Barone, Giampaolo

AU - Lo Bosco, Giosuè

AU - Nussberger, Stephan

AU - Eisler, Stephan A.

AU - Kuban-Jankowska, Alicja

AU - Perricone, Ugo

AU - Gorska-Ponikowska, Magdalena

PY - 2018

Y1 - 2018

N2 - 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: Llactate induced mitochondrial biogenesis pathway via upregulation of COXI. 2-ME inhibited mitochondrial biogenesis via regulation of PGC-1�, 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.

AB - 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: Llactate induced mitochondrial biogenesis pathway via upregulation of COXI. 2-ME inhibited mitochondrial biogenesis via regulation of PGC-1�, 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.

KW - 2-Methoxyestradiol; Mitochondrial biogenesis; Osteosarcoma; Sirtuin 3; Succinate dehydrogenase; Biochemistry; Molecular Biology; Genetics; Cancer Research

UR - http://hdl.handle.net/10447/256936

UR - http://cgp.iiarjournals.org/content/15/1/73.full.pdf+html

M3 - Article

VL - 15

SP - 73

EP - 89

JO - CANCER GENOMICS & PROTEOMICS.

T2 - CANCER GENOMICS & PROTEOMICS.

JF - CANCER GENOMICS & PROTEOMICS.

SN - 1109-6535

ER -