13-cis Retinoic Acid Induces Apoptosis and Cell Cycle Arrest in Human SEB-1 Sebocytes

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.

Early gene changes induced by isotretinoin in the skin provide clues to its mechanism of action

“…11,12 Since 13-cis RA is the most potent agent available to reduce severe inflammatory acne, it is possible that the upregulation of serpins, which in turn, scavenge pro-inflammatory proteins, mediates the anti-inflammatory effect of 13-cis RA. In support of this hypothesis, previous HPLC studies demonstrated that 13-cis RA can be isomerized to ATRA within sebocytes 9 and it has been shown that SERPINA5 is capable of binding ATRA in vitro and may function in retinoid transport. 13,14 13-cis RA significantly increased expression of multiple members of the solute carrier family of proteins.…”

“…[2][3][4][5] The increase in expression of TIG1 induced by 13-cis RA may mediate the known effects of this drug in chemoprevention of skin cancer in addition to the known suppressive effects on sebocyte proliferation. [6][7][8][9] Furthermore, genes encoding both serine proteases and serine protease inhibitors were upregulated by 13-cis RA at one-week. Serine protease inhibitors (serpins) are involved in tissue remodeling and control of inflammation.…”

Role of FGFR2-signaling in the pathogenesis of acne

“…100 Intriguingly, retinoids which are known to inhibit sebocyte differentiation and downregulate FGFR2b-signaling have been shown to reduce Gli transcriptional activity in cultured keratinocytes. [119][120][121] This could lead to retinoid-induced downregulation of MC5R expression and lipogenesis.…”

Between the Bioactive Extracts of Edible Mushrooms and Pharmacologically Important Nanoparticles: Need for the Investigation of a Synergistic Combination - A Mini Review

“…This has been demonstrated to be effective for the treatment of the diseases of the HF, for an increased local bioavailability of active pharmaceutical ingredient (API) at their drug target. Nelson et al identified that isotretinoin can cause the arrest of a cell cycle as well as apoptosis in sebocytes [58], whereas Messenger and Rundegren reported that minoxidil activated the synthesis of the vascular endothelial growth factor and prostaglandin in the dermal papilla [59], cyclosporine A was also reported by Takahashi and Kamimura to support the growth of hair epithelial cell growth [60]. In dermal therapy, the major objective is to reduce the systemic side effects of drugs through local administration of the API.…”