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.

ABSTRACT

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.