All-trans retinoic acid induces cell-cycle arrest in human cutaneous squamous carcinoma cells by inhibiting the mitogen-activated protein kinase-activated protein 1 pathway

Summary Background All‐trans retinoic acid (ATRA) has been tried for the treatment and prevention of a number of epithelial cancers. However, the precise mechanism by which ATRA inhibits the growth of cutaneous squamous cell carcinoma (cSCC) remains elusive. Aims To determine the suppressive effects of ATRA on the human cSCC cell line SCL‐1, and explore the possible mechanisms involved. Methods SCL‐1 cells were treated with ATRA, then cell proliferation was measured by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay, while apoptosis and cell cycle progression were analysed by flow cytometry. Protein levels of cell‐cycle regulatory proteins and the activation of extracellular signal‐regulated kinase (ERK) and Jun kinase (JNK) were detected by western blotting analysis. Transcriptional activity of activator protein (AP)‐1 was examined by luciferase reporter assay. Results ATRA inhibited the proliferation of SCL‐1 cells and had modest proapoptotic effects. ATRA also induced G1 cell‐cycle arrest, inhibited the expression of cyclin D1/cyclin‐dependent kinase (CDK)4 and cyclinE/CDK2, and increased the expression of the cyclin‐dependent kinase inhibitors p21 and p27. In addition, ATRA significantly decreased the phosphorylation of ERK1/2 and JNK1/2, and inhibited AP‐1 transcriptional activity. Conclusions ATRA induces cell‐cycle arrest in human cSCC cells by inhibiting the mitogen‐activated protein kinase (MAPK)–AP1 pathway, and could be effective in the prevention and chemotherapy of human cSCC.