Touma SE, Perner S, Rubin MA, Nanus DM, Gudas LJRetinoid metabolism and ALDH1A2 (RALDH2) expression are altered in the transgenic adenocarcinoma mouse prostate model. Biochem Pharmacol 78: 1127-1138

Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
Biochemical pharmacology (Impact Factor: 5.01). 07/2009; 78(9):1127-38. DOI: 10.1016/j.bcp.2009.06.022
Source: PubMed


Retinoids, which include vitamin A (retinol) and metabolites such as retinoic acid, can inhibit tumor growth and reverse carcinogenesis in animal models of prostate cancer. We analyzed retinoid signaling and metabolism in the TRAMP (transgenic adenocarcinoma mouse prostate) model. We detected increased retinol and retinyl esters in prostates pooled from 24 to 36 week TRAMP transgenic positive mice compared to nontransgenic littermates by HPLC. We used quantitative RT-PCR to measure transcripts for genes involved in retinoid signaling and metabolism, including ALDH1A1, ALDH1A2, ALDH1A3, CYP26A1, LRAT, and RARbeta(2), in prostate tissue from TRAMP positive (+) and age-matched littermate control mice ranging from 18 to 36 weeks. Transcript levels of ALDH1A1, a putative stem cell marker, were decreased in ventral and lateral lobes of prostates from TRAMP mice compared to age-matched, nontransgenic mice. ALDH1A2 (RALDH2) mRNA levels in dorsal and anterior lobes of TRAMP+ mice were lower than in age-matched (24 week) nontransgenic mice. We detected lower RARbeta(2) mRNA levels in dorsal prostate lobes of 36 week TRAMP mice relative to nontransgenic mice. We detected high levels of ALDH1A2 protein in the cytoplasm and nucleus in nontransgenic murine prostate paraffin sections, and lower ALDH1A2 protein levels in all prostate lobes of TRAMP mice compared to nontransgenic mice by immunohistochemistry. We also detected much lower cytoplasmic ALDH1A2 protein levels in all human prostate cancer paraffin sections stained (19 total) relative to normal human prostate tissue on the same sections. Our data indicate that this reduction in ALDH1A2 protein is an early event in human prostate cancer.

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    • "Although we observe that RA is required for prostate growth at later stages, ALDH expression in the UGM decreases with age. ALDH1a1 has been shown to be expressed in adult human prostate epithelia and ALDH1a2 has been detected in adult prostate epithelia of mouse and man (Kim et al., 2005; Li et al., 2010; Touma et al., 2009). This suggests a complex role for this signaling pathway as the prostate differentiates and matures. "
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    ABSTRACT: The mammalian urogenital sinus (UGS) develops in a sex specific manner, giving rise to the prostate in the male and the sinus vagina in the embryonic female. Androgens, produced by the embryonic testis, have been shown to be crucial to this process. In this study we show that retinoic acid signaling is required for the initial stages of bud development from the male UGS. Enzymes involved in retinoic acid synthesis are expressed in the UGS mesenchyme in a sex specific manner and addition of ligand to female tissue is able to induce prostate-like bud formation in the absence of androgens, albeit at reduced potency. Functional studies in mouse organ cultures that faithfully reproduce the initiation of prostate development indicate that one of the roles of retinoic acid signaling in the male is to inhibit the expression of Inhba, which encodes the βA subunit of Activin, in the UGS mesenchyme. Through in vivo genetic analysis and culture studies we show that inhibition of Activin signaling in the female UGS leads to a similar phenotype to that of retinoic acid treatment, namely bud formation in the absence of androgens. Our data also reveals that both androgens and retinoic acid have extra independent roles to that of repressing Activin signaling in the development of the prostate during fetal stages. This study identifies a novel role for retinoic acid as a mesenchymal factor that acts together with androgens to determine the position and initiation of bud development in the male UGS epithelia.
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    • "The RA-receptor β (Rarβ) is also down-regulated in STOSE cells (−10.80 fold) suggesting multiple aspects of RA signaling are lost. RA signaling has been shown to crosstalk with Wnt/β-catenin signaling and Aldh1a2 has also been identified as a tumor suppressor in prostate cancer, loss of which is an early event in the disease (64, 65). Further study of Alhd1a2, RA signaling, and the crosstalk between RA and Wnt/B-catenin signaling may help determine the mechanisms leading to transformation and tumorigenesis in HGSC. "
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    • "Aldh1a2- immunoreactivity has been used to determine the subcellular distribution of the protein and has located Aldh1a2 to the cytoplasm of human prostate epithelial cells and smooth muscle cells in the mouse. In addition, mammalian Aldh1a2 protein is predicted , based on amino acid sequence, to locate to the cytoplasm (Berggren et al., 2001; Touma et al., 2009). It will be interesting to determine the subcellular localization of Aldh1a2 in the various cell types highlighted by aldh1a2:gfp. "
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