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.