retinaldehyde and Prostatic-Neoplasms

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.

Topics: Aldehyde Dehydrogenase; Androgens; Calcium-Calmodulin-Dependent Protein Kinases; Cell Line, Tumor; Cytochrome P-450 Enzyme System; Dihydrotestosterone; Estradiol; Flavonoids; Gene Expression Regulation, Enzymologic; Humans; Isoenzymes; Male; Metribolone; Prostatic Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retinaldehyde; Retinoic Acid 4-Hydroxylase; RNA, Messenger; RNA, Small Interfering; src-Family Kinases; Tretinoin

Vitamin A (retinol) and its derivatives, the retinoids, have been implicated as chemopreventive and differentiating agents in a variety of cancers, including that of the prostate. Very little is known about the physiological role of retinoids in the prostate. Here we show that normal prostate, benign prostate hyperplasia (BPH), and prostate carcinoma tissues contain endogenous retinol and its biologically active metabolite retinoic acid. In our studies, the concentration of retinol was 2-fold elevated in BPH compared with the other two tissues. In contrast, prostate carcinoma tissue contained five to eight times less retinoic acid than normal prostate or BPH. Moreover, we found that prostate tissue expresses dehydrogenases capable of converting retinol to retinoic acid through retinaldehyde as an intermediate. Formation of retinal from retinol takes place in microsomes, and the conversion of retinal to retinoic acid occurs in the cytosol. Furthermore, we found that the nuclear retinoic acid receptors alpha, beta, and gamma are expressed in normal and tumor samples. These studies establish a role for retinoids in the physiology of the prostate and possibly also in the pathophysiology of prostate cancer.

Topics: Base Sequence; Chromatography, High Pressure Liquid; Humans; Male; Molecular Probes; Molecular Sequence Data; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Retinoic Acid; Reference Values; Retinaldehyde; Retinoids; RNA, Messenger; Tretinoin; Vitamin A