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Androgen regulation of the retinoic acid biosynthesis‐related aldehyde dehydrogenase 1A3 gene in the human prostate cancer cell LNCaP
Author(s) -
Trasino Steven E.,
Harrison Earl H.,
Wang Thomas T.Y.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a253-a
Subject(s) - lncap , dihydrotestosterone , retinoic acid , androgen receptor , endocrinology , prostate cancer , biology , androgen , medicine , cancer research , aldehyde dehydrogenase , chemistry , biochemistry , cancer , enzyme , gene , hormone
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 prostate cancer epithelial cells (LNCaP). In the present study we attempted to identify if any of the three ALDH/RA synthesis enzymes are androgen responsive and how this may affect retinoid‐mediated events in LNCaP cells. We demonstrated that exposure of LNCaP cells to the androgen dihydrotestosterone (DHT) resulted in a five‐fold increase of ALDH1A3 mRNA levels compared to the untreated controls. 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 anti‐androgen Casodex and small interfering RNA (siRNA) for AR, support the premise that ALDH1A3 regulation by DHT is mediated by AR. Consistently, DHT‐treated LNCaP cell lysates showed an eight‐fold increase in retinaldehyde‐dependent NAD+ reduction activity compared to controls. Furthermore, treatment of LNCaP cells with all trans‐retinal (RAL) in the presence of DHT resulted in a significant up‐regulation of the RA‐inducible RA metabolizing enzyme CYP26A1 mRNA, a surrogate endpoint for RA bioactivity and metabolism. Taken together, these data suggest that: androgen regulation of the ALDH1A3 gene is via direct action through the AR, and DHT up‐regulation of ALDH1A3 can increase the oxidation of RAL to RA and indirectly affect RA bioactivity and metabolism.