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13 - cis - Retinoic acid induces apoptosis and cell cycle arrest in human SEB - 1 sebocytes

The Jake Gittlen Cancer Research Foundation, The Pennsylvania State University College of Medicine, Hershey, 17033, USA.
Journal of Investigative Dermatology (Impact Factor: 6.37). 11/2006; 126(10):2178-89. DOI: 10.1038/sj.jid.5700289
Source: PubMed

ABSTRACT Isotretinoin (13-cis retinoic acid (13-cis RA)) is the most potent inhibitor of sebum production, a key component in the pathophysiology of acne, yet its mechanism of action remains largely unknown. The effects of 13-cis RA, 9-cis retinoic acid (9-cis RA), and all-trans retinoic acid (ATRA) on cell proliferation, apoptosis, and cell cycle proteins were examined in SEB-1 sebocytes and keratinocytes. 13-cis RA causes significant dose-dependent and time-dependent decreases in viable SEB-1 sebocytes. A portion of this decrease can be attributed to cell cycle arrest as evidenced by decreased DNA synthesis, increased p21 protein expression, and decreased cyclin D1. Although not previously demonstrated in sebocytes, we report that 13-cis RA induces apoptosis in SEB-1 sebocytes as shown by increased Annexin V-FITC staining, increased TUNEL staining, and increased cleaved caspase 3 protein. Furthermore, the ability of 13-cis RA to induce apoptosis cannot be recapitulated by 9-cis RA or ATRA, and it is not inhibited by the presence of a retinoid acid receptor (RAR) pan-antagonist AGN 193109. Taken together these data indicate that 13-cis RA causes cell cycle arrest and induces apoptosis in SEB-1 sebocytes by a RAR-independent mechanism, which contributes to its sebosuppressive effect and the resolution of acne.

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    • "Isotretinoin induces cell cycle arrest in SEB-1 sebocytes with increased expression of the cell cycle inhibitor p21 37. Upregulation of the FoxO1 target gene p21 could thus explain isotretinoin-induced sebocyte apoptosis 38. "
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    • "In the sebaceous gland, RA decreases basal sebocyte proliferation, prohibits sebocyte terminal differentiation, induces sebocyte apoptosis , and suppresses sebum production up to 90% (Nelson et al., 2006). These effects appear to be mediated through receptor-dependent and ‐independent actions (Nelson et al., 2006; Tsukada et al., 2000) and alterations in gene expression (Nelson et al., 2008). In addition, RA may suppress androgen receptors (Ubels et al., 2002, 2003) and inhibit retinol dehydrogenase-4 in sebaceous glands (Karlsson et al., 2003), which would diminish the local, intracrine production of dihydrotestosterone (DHT). "
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    • "This drug acts to suppress acne in multiple ways, reducing sebaceous gland secretion and size, possibly by inhibiting proliferation and inducing apoptosis of sebocytes (Nelson et al. 2006) and also acting as an anti-inflammatory agent blocking the migration of polymorphonuclear leukocytes into the skin (Wozel et al. 1991). It is believed to act by isomerisation to all-trans-RA in tissues (Shih et al. 1986; Tsukada et al. 2000), which then activates specific receptors for retinoic acid (Nelson et al. 2009; Rochette-Egly and Germain 2009). "
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