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Metabolism and regulation of gene expression by 4‐oxoretinol versus all‐ trans retinoic acid in normal human mammary epithelial cells
Author(s) -
Liu Limin,
Derguini Fadila,
Gudas Lorraine J.
Publication year - 2009
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21824
Subject(s) - retinoic acid , intracellular , biology , gene expression , retinoid , microbiology and biotechnology , cell growth , receptor , gene , biochemistry
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 receptorβ2 (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 µM tRA treated HMECs all of the tRA was found intracellularly, and tRA was the predominant intracellular retinoid. In 1 µM 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 µM 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. J. Cell. Physiol. 220: 771–779, 2009. © 2009 Wiley‐Liss, Inc.