title: Mitochondrial-associated nitric oxide synthase activity inhibits cytochrome c oxidase: implications for breast cancer.
abstract: Nitric oxide (NO) is produced and nitric oxide synthase (NOS) activity is expressed in many types of tumor cells, but their precise role in tumor proliferation has not been clearly elucidated. Recently, it has been observed that patients with triple-negative breast tumors expressing NOS have a significantly worse prognosis compared to those that do not express any NOS. We observed that NOS activity was associated with the mitochondria in two breast cancer cell lines, ZR-75-30 and BT-474, compared with another NO-producing benign breast epithelial cell line, MCF-12F, in which no significant mitochondrial-associated NOS activity was detected. The rate of proliferation of the malignant cells expressing mitochondrial-associated NOS was decreased in the presence of an inhibitor of NO synthesis, but it had no effect on the normal breast epithelial cells, MCF-12F, which also expressed NOS, but not associated with mitochondria. The basal rate of proliferation was not affected by ODQ, an inhibitor of soluble guanylate cyclase, indicating that the effects of the endogenous NO produced by the malignant cell lines on proliferation are cGMP independent. Our results indicate that mitochondrial-associated NOS activity exhibited by the cancer cell lines ZR-75-30 and BT-474 inhibited cytochrome c oxidase, resulting in increased production of hydrogen peroxide (H2O2), which inhibited protein phosphatase 2A activity. This resulted in the maintenance of Akt and ERK1/2 in a phosphorylated state, leading to cell proliferation.
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. ssen@mednet.ucla.edu
authors.forename: Suvajit
authors.initials: S
authors.lastname: Sen
authors.forename: Brian
authors.initials: B
authors.lastname: Kawahara
authors.forename: Gautam
authors.initials: G
authors.lastname: Chaudhuri
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D003576:Electron Transport Complex IV; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D054648:Protein Phosphatase 2; D006162:Guanylate Cyclase; D019331:NG-Nitroarginine Methyl Ester