13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes.
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.
Nelson
Amanda M
AM
The Jake Gittlen Cancer Research Foundation, The Pennsylvania State University College of Medicine, Hershey, 17033, USA.
Gilliland
Kathryn L
KL
Cong
Zhaoyuan
Z
Thiboutot
Diane M
DM
D000077556:Alitretinoin; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D020287:In Situ Nick-End Labeling; D015474:Isotretinoin / Q000737:chemistry / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology; D012627:Sebaceous Glands / Q000166:cytology / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009281:Naphthalenes; D019938:Cyclin D1; D000077556:Alitretinoin; D014212:Tretinoin; D004247:DNA; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D015474:Isotretinoin; C096920:AGN 193109