Inter-related in vitro effects of androgens, fatty acids and oxidative stress in prostate cancer: a mechanistic model supporting prevention strategies
Autor: | Brian C. Wilson, Shengjun Qiao, Jehonathan H. Pinthus, Lauren Monardo, Bobby Shayegan, Helen Lin, Gurmit Singh, Pierre Laflamme, Inna Bryskin, Jian-Ping Lu |
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Rok vydání: | 2010 |
Předmět: |
Mitochondrial ROS
Male Cancer Research medicine.medical_specialty Neoplasms Hormone-Dependent Bicalutamide medicine.drug_class Mitochondrion Biology urologic and male genital diseases medicine.disease_cause Gene Expression Regulation Enzymologic Tosyl Compounds Internal medicine Cell Line Tumor Nitriles medicine Humans Anilides Carnitine RNA Messenger Testosterone Congeners chemistry.chemical_classification Reactive oxygen species Carnitine O-Palmitoyltransferase Uncoupling Agents Fatty Acids Prostatic Neoplasms Androgen Antagonists Free Radical Scavengers Metribolone Androgen Mitochondria Up-Regulation Androgen receptor Oxidative Stress Endocrinology Oncology chemistry Reactive Oxygen Species Oxidation-Reduction Oxidative stress medicine.drug |
Zdroj: | International journal of oncology. 37(4) |
ISSN: | 1791-2423 |
Popis: | Oxidation of mitochondrial fatty acids (FA) results in the generation of reactive oxygen species (ROS) which have been postulated to play a key role in the initiation and progression of prostate cancer (PC). We previously reported that androgens increase FA uptake into PC cells. We thus examined if androgens that are known to induce ROS generation regulate FA oxidation in PC cells. The effects of the androgen-depleted medium, R1881 (synthetic androgen) and/or androgen receptor blocker, bicalutamide were examined in the human androgen-responsive but not dependent 22rv1 cells. R1881 supplementation significantly increased mitochondrial FA oxidation ((14)C-radiolabeled FA degradation studies), resulting in increased ROS production. Androgens increased the mRNA levels of carnitine palmitoyltransferase (CPT1), the rate limiting enzyme in the process of mitochondrial FA oxidation. Treatment with R1881 and bicalutamide inhibited these androgen regulated effects. Inhibition of mitochondrial ROS generation by two different inhibitors, rotenone and thenoyltrifluoroacetone, eliminated the androgen-induced ROS generation, to the same level as in cells deprived of androgens or treated with R1881 and bicalutamide. Taken together, androgens increase the mitochondrial oxidation of FA, leading to increased production of ROS that is associated with prostate cell proliferation and mutagenesis. These results therefore support the rationale for PC prevention using 5-alpha reductase inhibitors, dietary restrictions or anti-oxidants, each of which has different inhibitory but complementary effects. |
Databáze: | OpenAIRE |
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