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Decreased mitochondrial nitric oxide synthase activity and hydrogen peroxide relate persistent tumoral proliferation to embryonic behavior

Galli, S; Labato, MI; Bal de Kier, JE; Carreras, MC; Poderoso, JJ; (2003) Decreased mitochondrial nitric oxide synthase activity and hydrogen peroxide relate persistent tumoral proliferation to embryonic behavior. Cancer Res. , 63 (19) pp. 6370-6377.

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Abstract

Differential expression and activity of constitutive mitochondrial nitric oxide synthase (mtNOS) in the mitochondrial compartment is followed by significant variations in matrix nitric oxide (NO) steady-state concentration. The mitochondrial utilization of NO involves the production of superoxide anion and H(2)O(2), a species freely diffusible outside the mitochondria that participates in the modulation of cell proliferation and apoptosis and in cell transformation and cancer. On these bases, we analyzed the modulation of mtNOS in the frame of cellular redox state in M3, MM3, and P07 murine tumors and their respective cell lines, as compared with normal proliferating and quiescent tissues. The results showed that: (a) tumoral and proliferating mitochondria only retain 10-50% of the activity of complexes I, II-III, and IV and Mn-SOD of quiescent tissues; (b) normal proliferating tissues, like embryonic liver or pregnant mammary gland, have 10-20% of mtNOS expression and activity and mitochondrial H(2)O(2) yield than quiescent nonproliferating tissues; (c) similarly but irrespective of mtNOS expression, tumoral mitochondria have no >5% of mtNOS activity and H(2)O(2) yield of mature tissues; and (d) in opposition to stable tissues, both tumoral and normal proliferating cells exhibit high cyclin D1 expression and low pro-apoptotic p38mitogen-activated protein kinase activity. Dually, H(2)O(2) stimulated tumor cell proliferation (<10 microM) or markedly inhibited it (>10 microM) with parallel variations of cyclin D1, phospho-extracellular-regulated kinase1/2, and phospho-p38mitogen-activated protein kinase. It is surmised that decreased oxidative phosphorylation, defective tumoral mtNOS, and low mitochondrial NO-dependent H(2)O(2) may be a platform to link persistent tumoral growth to embryonic behavior

Type: Article
Title: Decreased mitochondrial nitric oxide synthase activity and hydrogen peroxide relate persistent tumoral proliferation to embryonic behavior
Additional information: DA - 20031015 IS - 0008-5472 (Print) IS - 0008-5472 (Linking) LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't RN - 136601-57-5 (Cyclin D1) RN - 31C4KY9ESH (Nitric Oxide) RN - BBX060AN9V (Hydrogen Peroxide) RN - EC 1.14.13.39 (Nitric Oxide Synthase) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM
Keywords: Adenocarcinoma, Animals, Apoptosis, biosynthesis, Cell Division, Cell Line, Cell Line,Tumor, Cell Proliferation, Cyclin D1, cytology, embryology, enzymology, Female, Hydrogen Peroxide, Liver, Mammary Neoplasms,Experimental, metabolism, Mice, Mice,Inbred BALB C, Mitochondria, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Nitric Oxide, Nitric Oxide Synthase, Oxidation-Reduction, Oxygen, p38 Mitogen-Activated Protein Kinases, pathology, Phosphorylation, physiology, Pregnancy, Rats, Rats,Wistar, Signal Transduction
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: http://discovery.ucl.ac.uk/id/eprint/1451816
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