Curcumin Induces Downregulation of E2F4 Expression and Apoptotic Cell Death in HCT116 Human Colon Cancer Cells; Involvement of Reactive Oxygen Species

Abstract

E2F transcription factors and their target genes have been known to play an important role in cell growth control. W e found that curcumin, a polyphenolic phytochemical isolated from the plant Curcuma longa, markedly suppressed E2F4 expression in HCT116 colon cancer cells. Hydrogen peroxide was also found to decrease E2F4 protein level, indicating the involvement of reactive oxygen species (ROS) in curucmin-induced downregulation of E2F4 expression. Involvement of ROS in E2F4 downregulation in response to curcumin was confirmed by the result that pretreatment of cells with N-acetylcystein (NAC) before exposure of curcumin almost completely blocked the reduction of E2F4 expression at the protein as well as mRNA level. Anti-proliferative effect of curcumin was also suppressed by NAC which is consistent to previous reports showing curcumin-superoxide production and induction of poly (ADP-ribose) polymerase (PARP) cleavage as well as apoptosis. Expression of several genes, cyclin A, p21, and p27, which has been shown to be regulated in E2F4-dependent manner and involved in the cell cycle progression was also affected by curcumin. Moreover, decreased (cyclin A) and increased (p21 and p27) expression of these E2F4 downstream genes by curcumin was restored by pretreatment of cells with NAC and E2F4 overexpression which is induced by doxycycline. In addition, E2F4 overexpression was observed to partially ameliorate curcumin-induced growth inhibition by cell viability assay. Taken together, we found curcumin-induced ROS down-regulation of E2F4 expression and modulation of E2F4 target genes which finally lead to the apoptotic cell death in HCT116 colon cancer cells, suggesting that E2F4 appears to be a novel determinant of curcumin-induced cytotoxicity.

Dietary myo-inositol modulates immunity through antioxidant activity and the Nrf2 and E2F4/cyclin signalling factors in the head kidney and spleen following infection of juvenile fish with Aeromonas hydrophila

“…The mechanisms underlying the inhibition of E2F4 and cyclin expression under MI deficiency are unknown but might be partially related to the increase in ROS. As mentioned above, ROS are involved in the down-regulation of E2F4 expression and the inhibition of the proliferation of HCT116 human colon cancer cells [35]. In the present study, we observed that MI deficiency caused an induction of ROS production in both the head kidney and spleen, which supported our hypothesis.…”

“…Furthermore, our previous study demonstrated that MI deficiency caused a decrease in the ROS scavenging ability in the intestines of juvenile Jian carp [6]. Kim and Lee reported that ROS are involved in down-regulation of E2F4 expression and the inhibition of the proliferation of HCT116 human colon cancer cells [35]. Recently, our laboratory cloned cyclin D, cyclin E and E2F4 from Jian carp; cyclin A was previously cloned by Liu et al (Genebank access No.…”

Involvement of ROS in Curcumin-induced Autophagic Cell Death

“…There have been several mechanisms to explain the antioxidant, antiinflammatory and anticancer effect of curcumin [25][26][27][28][29]. Autophagy which is designated as type II programmed cell death has also been reported to be an anticancer mechanism of curumin, resulting in the growth inhibition of a variety of malignant of cells such as chronic myeloid leukemia cells, malignant glioma cells, and oesophageal cancer cells [30][31][32].…”

GS28 Protects Neuronal Cell Death Induced by Hydrogen Peroxide under Glutathione-Depleted Condition

“…GSH plays a central role in maintaining redox homeostasis [4]. Elevated ROS elicit a variety of oxidative stress responses ranging from cell proliferation to growth arrest to cell death [5,6]. The particular outcome can vary depending on cell type as well as the concentration and duration of ROS exposure.…”