Esculetin, a phenolic compound, has been shown to inhibit the growth of colon
tumors in animal studies. However, the roles of signaling pathways and cell cycle regulation in the
esculetin-induced inhibition of
cancer cell growth, remain to be elucidated. The present study suggests a novel mechanism for the Ras/ERK1/2 pathway in
esculetin-treated human
colon cancer HCT116 cells. The treatment of cells with
esculetin resulted in significant growth inhibition and G1 phase cell cycle arrest, which led to the down-regulation of
cyclin and
cyclin-dependent kinase (CDK) expressions. This G1 phase cell cycle arrest was associated with the up-regulation of p27KIP expression. In addition, ERK1/2 was activated by
esculetin. The pre-treatment of cells with the MEK1/2-specific inhibitor,
PD98059, blocked the p27KIP expression induced by
esculetin. Blockage of the ERK1/2 function consistently prevented the inhibition of cell proliferation and decreased G1 phase cell cycle
protein levels. Furthermore, Ras activation was increased by the
esculetin treatment. Transient transfection of the dominant negative Ras (RasN17) mutant gene abolished both the ERK1/2 activity and p27KIP expression induced by
esculetin. Finally, the overexpression of RasN17 suppressed the
esculetin-induced reduction in cell proliferation and
cell cycle proteins. In conclusion, these results indicate that the Ras/ERK1/2 pathway is mediated by the p27KIP1 induction, leading to a reduction in
cyclin/CDK complexes in the
esculetin-induced inhibition of
colon cancer cell growth. Overall, these findings indicate that the molecular action of
esculetin has therapeutic potential for the treatment of colon
malignancies.