Abstract:
: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.
journal_name
J Cell Physioljournal_title
Journal of cellular physiologyauthors
Liu L,Derguini F,Gudas LJdoi
10.1002/jcp.21824subject
Has Abstractpub_date
2009-09-01 00:00:00pages
771-9issue
3eissn
0021-9541issn
1097-4652journal_volume
220pub_type
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