All-Trans Retinoic Acid Potentiates Antitumor Efficacy of Cisplatin by Increasing Differentiation of Cancer Stem-Like Cells in Cervical Cancer.

OBJECTIVE All-trans retinoic acid (ATRA), a derivative of vitamin A, has been reported to exert its synergistic antitumor effect with chemotherapy in various cancer types; however, its effect in cervical cancer remains unclear. The objective of this study was to investigate the antitumor effect of ATRA with or without cisplatin and elucidate its potential mechanisms in cervical cancer cells. METHODS Cell viability was determined by CCK-8 assay. Cell cycle and cell apoptosis were analyzed by flow cytometry. Caspase-3, cleaved caspase-3 and cell cycle-related proteins were detected by western blotting. Scratch wound-healing assay was performed to evaluate cell migration ability. The expression of CD44, a biomarker of cervical cancer stem-like cells, was determined by flow cytometry and western blotting. In addition, the activity of the Wnt signaling pathway was monitored by luciferase reporter assay and western blotting. RESULTS Compared with cisplatin treatment alone, combined use of ATRA and cisplatin significantly inhibited cell proliferation (p<0.01) and migration (p<0.01), and induced G0/G1 phase arrest (p<0.01) and apoptosis (p<0.05) in cervical cancer Hela cells. Furthermore, ATRA treatment also effectively induced differentiation of cancer stem-like cells as represented by reduced expression of CD44 and inhibited Wnt signaling pathway activity. CONCLUSIONS ATRA significantly enhanced the antitumor effect of cisplatin in cervical cancer cells, the mechanism of which might be attributed to its effect of inducing the differentiation of cancer stem-like cells.