Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in the androgen-responsive human prostate cancer cell line LNCaP.
Previous gene array data from our laboratory identified the retinoic acid (RA) biosynthesis enzyme aldehyde dehydrogenase 1A3 (ALDH1A3) as a putative androgen-responsive gene in human prostate cancer epithelial (LNCaP) cells. In the present study, we attempted to identify if any of the three ALDH1A/RA synthesis enzymes are androgen responsive and how this may affect retinoid-mediated effects in LNCaP cells. We demonstrated that exposure of LNCaP cells to the androgen dihydrotestosterone (DHT) results in a 4-fold increase in ALDH1A3 mRNA levels compared with the untreated control. The mRNA for two other ALDH1A family members, ALDH1A1 and ALDH1A2, were not detected and not induced by DHT in LNCaP cells. Inhibition of androgen receptor (AR) with both the antiandrogen bicalutamide and small interfering RNA for AR support that ALDH1A3 regulation by DHT is mediated by AR. Furthermore, specific inhibition of the extracellular signal-regulated kinase and Src family of kinases with PD98059 and PP1 supports that AR's regulation of ALDH1A3 occurs by the typical AR nuclear-translocation cascade. Consistent with an increase in ALDH1A3 mRNA, DHT-treated LNCaP cells showed an 8-fold increase in retinaldehyde-dependent NAD(+) reduction compared with control. Lastly, treatment of LNCaP with all-trans retinal (RAL) in the presence of DHT resulted in significant up-regulation of the RA-inducible, RA-metabolizing enzyme CYP26A1 mRNA compared with RAL treatment alone. Taken together, these data suggest that (i) the RA biosynthesis enzyme ALDH1A3 is androgen responsive and (ii) DHT up-regulation of ALDH1A3 can increase the oxidation of retinal to RA and indirectly affect RA bioactivity and metabolism.
Trasino
Steven E
SE
Phytonutrients Laboratory, Agricultural Research Service, USDA, Beltsville, MD 20705, USA.
Harrison
Earl H
EH
Wang
Thomas T Y
TT
D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000728:Androgens / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D011471:Prostatic Neoplasms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012172:Retinaldehyde / Q000494:pharmacology; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D000728:Androgens; D005419:Flavonoids; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013196:Dihydrotestosterone; D015741:Metribolone; D004958:Estradiol; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D000444:Aldehyde Dehydrogenase; D019061:src-Family Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D012172:Retinaldehyde; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one