Decreased mitochondrial nitric oxide synthase activity and hydrogen peroxide relate persistent tumoral proliferation to embryonic behavior.
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.
Galli
Soledad
S
Laboratory of Oxygen Metabolism, University Hospital, Córdoba 2351, CP 1120, University of Buenos Aires, 1120 Buenos Aires, Argentina.
Labato
Mariana Inés
MI
Bal de Kier Joffé
Elisa
E
Carreras
María Cecilia
MC
Poderoso
Juan José
JJ
D000230:Adenocarcinoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000201:enzymology* / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010084:Oxidation-Reduction; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D019938:Cyclin D1; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases