Metabolism and regulation of gene expression by 4-oxoretinol versus all-trans retinoic acid in normal human mammary epithelial cells.

TitleMetabolism and regulation of gene expression by 4-oxoretinol versus all-trans retinoic acid in normal human mammary epithelial cells.
Publication TypeJournal Article
Year of Publication2009
AuthorsLiu L, Derguini F, Gudas LJ
JournalJ Cell Physiol
Date Published2009 Sep
KeywordsBiological Transport, Cell Proliferation, Cells, Cultured, Chromatography, High Pressure Liquid, Epithelial Cells, Female, Gene Expression Profiling, Gene Expression Regulation, Humans, Mammary Glands, Human, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Time Factors, Transcription, Genetic, Tretinoin, Vitamin A

We previously demonstrated that 4-oxoretinol (4-oxo-ROL) activated retinoic acid receptors (RARs) in F9 stem cells. We showed that 4-oxo-ROL inhibited the proliferation of normal human mammary epithelial cells (HMECs). To understand the mechanisms by which 4-oxo-ROL regulates HMEC growth we examined gene expression profiles following 4-oxo-ROL or all-trans retinoic acid (tRA). We also compared growth inhibition by tRA, 4-oxo-ROL, or 4-oxo-RA. All three retinoids inhibited HMEC proliferation. Gene expression analyses indicated that 4-oxo-ROL and tRA modulated gene expression in closely related pathways. The expression of many genes, e.g. ATP-binding cassette G1 (ABCG1); adrenergic receptorbeta2 (ADRB2); ras-related C3 botulinum toxin substrate (RAC2); and short-chain dehydrogenase/reductase 1 gene (SDR1) was changed after 4-oxo-ROL or tRA. Metabolism of these retinoids was analyzed by high-performance liquid chromatography (HPLC). In 1 microM tRA treated HMECs all of the tRA was found intracellularly, and tRA was the predominant intracellular retinoid. In 1 microM 4-oxo-ROL treated HMECs most 4-oxo-ROL was esterified to 4-oxoretinyl esters, no tRA was detected, and 4-oxo-ROL and 4-oxo-RA were observed intracellularly. In 1 microM 4-oxoretinoic acid (4-oxo-RA) treated HMECs little intracellular 4-oxo-RA was detected; most 4-oxo-RA was in the medium. Our results indicate that: (a) 4-oxo-ROL regulates gene expression and inhibits proliferation of HMECs; (b) 4-oxo-ROL and tRA regulate some of the same genes; (c) more tRA is found in cells, as compared to 4-oxoretinoic acid, when each drug is added at the same concentration in the medium; and (d) the mechanism by which 4-oxo-ROL exerts its biological activity does not involve intracellular tRA production.

Alternate JournalJ. Cell. Physiol.
PubMed ID19492420
PubMed Central IDPMC3315369
Grant ListR01 CA077509-05 / CA / NCI NIH HHS / United States
T32 CA062948 / CA / NCI NIH HHS / United States
R01CA77509 / CA / NCI NIH HHS / United States