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United States Department of Agriculture

Agricultural Research Service

Title: Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in androgen responsive human prostate cancer cell LNCaP.

Authors
item Trasino, Steven
item Harrison, Earl - OHIO STATE UNIV.
item Wang, Thomas

Submitted to: Experimental Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 8, 2007
Publication Date: June 1, 2007
Citation: Trasino, S.E., Harrison, E.H., Wang, T.T. 2007. Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in androgen responsive human prostate cancer cell LNCaP. Experimental Biology and Medicine (Maywood). 232(6):762-771.

Interpretive Summary: Androgen (a male sex steroid hormone) is exposed to changes in retinoic acid, a biologically active compound-derived from Vitamin A and carotenoids. Metabolism is known risk factor in the development of prostate cancer. However, the mechanisms underlying these effects remain unclear. We hypothesized that androgen may promote prostate cancer by influencing retinoic acid metabolisms. In the present study, we examine the interaction of androgen and the metabolisms of retinoic acid using a prostate cancer cell culture model. We found that androgen can indeed influence the degradation of vitamin A and retinoic acid through a mechanisms involving sequential activation of vitamin A and the retinoic processing enzymes aldehyde hydrogenase 1A3 and CYP 26A. Because retinoic acid is necessary for normal prostate development, our results suggest that androgen regulation of retinoic acid metabolism may be a mechanism that can lead to prostate cancer development. This work provides novel information for cancer research scientists regarding the interactions and mechanisms of action of steroid hormones and metabolisms of health-promoting phytochemicals, such as carotenoids and will serve as important bases for future designs of cancer preventive strategy.

Technical Abstract: 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 ALDH1A/RA synthesis enzymes are androgen responsive and how this may affect retinoid-mediated effects in LNCaP cells. We demonstrate that exposure of LNCaP cells to the androgen DHT results in a five-fold increase of ALDH1A3 mRNA levels compared to 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 anti-androgen Casodex and small interfering RNA (siRNA) for AR, support that ALDH1A3 regulation by DHT is mediated by AR. Furthermore, specific inhibition of the ERK and Src-family kinases with PD98059 and PP1 supports that ARG 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 to control. Lastly, treatment of LNCaP with all trans-retinal in the presence of DHT resulted in a significant up-regulation of RA-inducible, RA-metabolizing enzyme CYP26A1 mRNA compared to RAL treatment alone. Taken together, these data suggest that: 1) The RA biosynthesis enzyme ALDH1A3 is androgen responsive, and 2) DHT up-regulation of ALDH1A3 can increase the oxidation of retinal to RA and indirectly affect RA bioactivity and metabolism.

Last Modified: 10/20/2014
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