[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Jan 2011 · Oncology Reports
[Show abstract][Hide abstract] ABSTRACT: The thorns of Gleditsia sinensis have traditionally been used in the treatment of several diseases, which includes their use as anti-tumor agents, but there has been no scientific evidence of this anti-tumor effect. However, the present study has identified a novel mechanism for the anti-tumor effect of Gleditsia sinensis thorns in the treatment of colon cancer. Treatment with the ethanol extract of Gleditsia sinensis thorns (EEGS) resulted in significant growth inhibition together with G2/M-phase cell cycle arrest at a dose of 600 microg/ml (IC50) in HCT116 cells. In addition, treatment with EEGS induced p27 expression and down-regulated expression of cyclins and cyclin-dependent kinases. Moreover, EEGS treatment induced phosphorylation of extracellular signal-regulated kinases (ERK), p38 MAP kinase and JNK (c-Jun N-terminal kinases). Among the pathways examined, only PD98059 (ERK-specific inhibitor) abolished EEGS-dependent p27 expression. Similarly, suppression of ERK function reversed EEGS-mediated cell proliferation inhibition and decreased cell cycle proteins. In addition, tumor necrosis factor-alpha (TNF-alpha)-induced matrix metalloproteinase-9 (MMP-9) expression was inhibited by EEGS treatment via decreased transcriptional activity of both activator protein-1 (AP-1) and nuclear factor-kappaB. Finally, EEGS treatment significantly reduced tumor sizes in HCT116 cell-xenografted tumor tissues, which was associated with the changed levels of ERK phosphorylation, p27 and MMP-9 expression. Overall, these results have identified a novel molecular mechanism for EEGS in the treatment of colon cancer and might provide a theoretical basis for the potential therapeutic use of EEGS in the treatment of malignancies.
No preview · Article · Dec 2009 · Oncology Reports
[Show abstract][Hide abstract] ABSTRACT: Piceatannol (3,5,3',4'-tetrahydroxy- trans-stilbene), a resveratrol analogue, is a polyphenol present in the skins of grapes and in wine and other foods. The present study aimed to investigate for the first time the cardioprotective effects of piceatannol on vascular smooth muscle cells (VSMC). The treatment of cells with piceatannol inhibited cell proliferation by reducing extracellular signal-regulated kinase (ERK) 1/2 and JNK activity in cultured VSMC in the presence of tumor necrosis factor-alpha (TNF-alpha). These inhibitory effects were also associated with G1 cell cycle arrest, and resulted in a decrease in cyclin-dependent kinases (CDKs) and cyclins. Piceatannol treatment strongly induced the expression of p21WAF1 via independence of p27KIP and p53 expression. The effect of piceatannol was not restricted to cell proliferation, as TNF-alpha-induced invasion and migration was also suppressed in VSMC. Moreover, piceatannol treatment strongly decreased matrix metalloproteinase-9 (MMP-9) expression and promoter activity in a dose-dependent manner in response to TNF-alpha. It was further demonstrated that piceatannol abrogated the transcriptional activity of nuclear factor kappa B (NF-kappaB), an important nuclear transcription factor involved in MMP-9 expression. Overall, these results demonstrate that piceatannol inhibits proliferation and migration of VSMC treated with TNF-alpha. Therefore, piceatannol may be an effective therapeutic approach to treat atherosclerosis.
No preview · Article · Aug 2009 · Toxicology in Vitro