Inter-related in vitro effects of androgens, fatty acids and oxidative stress in prostate cancer: a mechanistic model supporting prevention strategies.
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.
Lin
Helen
H
Juravinski Cancer Centre, Hamilton, Ontario L8V 5C2, Canada.
Lu
Jian-Ping
JP
Laflamme
Pierre
P
Qiao
Shengjun
S
Shayegan
Bobby
B
Bryskin
Inna
I
Monardo
Lauren
L
Wilson
Brian C
BC
Singh
Gurmit
G
Pinthus
Jehonathan H
JH
D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D009570:Nitriles / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D045165:Testosterone Congeners / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000494:pharmacology; D015854:Up-Regulation
D000726:Androgen Antagonists; D000813:Anilides; D005227:Fatty Acids; D016166:Free Radical Scavengers; D009570:Nitriles; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D045165:Testosterone Congeners; D014105:Tosyl Compounds; D014475:Uncoupling Agents; D015741:Metribolone; C053541:bicalutamide; D002334:Carnitine O-Palmitoyltransferase