p21Waf1/Cip1 Expression by Curcumin in U-87MG Human Glioma Cells: Role of Early Growth Response-1 Expression

Abstract

Curcumin, a natural compound, is a well-known chemopreventive agent with potent anticarcinogenic activity in a wide variety of tumor cells. Curcumin inhibits cancer cell proliferation in part by suppressing cyclin D1 and inducing expression of the cyclin-dependent kinase inhibitor p21Waf1/Cip1 . Both p53-dependent and p53-independent mechanisms regulate p21Waf1/Cip1 expression, but the mechanism by which curcumin regulates p21Waf1/Cip1 expression remains unknown. Here, we report that transcription of the p21Waf1/Cip1 gene is activated by early growth response-1 (Egr-1) independently of p53 in response to curcumin treatment in U-87MG human glioblastoma cells. Egr-1 is a transcription factor that helps regulate differentiation, growth, and apoptosis in many cell types. Egr-1 expression is induced by curcumin through extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase (JNK), but not the p38, mitogen-activated protein kinase (MAPK) pathways, which mediate the transactivation of Elk-1. Transient expression of Egr-1 enhanced curcumin-induced p21 Waf1/Cip1 promoter activity, whereas suppression of Egr-1 expression by small interfering RNA abrogated the ability of curcumin to induce p21 Waf1/Cip1 promoter activity. In addition, stable knockdown of Egr-1 expression in U-87MG cells suppressed curcumin-induced p21 expression. Our results indicate that ERK and JNK MAPK/Elk-1/Egr-1 signal cascade is required for p53-independent transcriptional activation of p21 Waf1/Cip1 in response to curcumin in U-87MG human glioblastoma cells. [Cancer Res 2008;68(5):1369-77]

17-(Allylamino)-17-Demethoxygeldanamycin Combination with Curcumin Selectively Targets Mitogen Kinase Pathway in A Human Neuroblastoma Cell Line

“…Usually only one form of dual phopshorylated ERK exists in the cell with greater specificity, which translocates to the nucleus and activates certain transcriptional factors. In agreement with curcumin induced ERK and JNK pathways [33], we report ERK1 activation and its nuclear localization with 17AAG and curcumin, however, the combination has significantly inhibited its activation and nuclear translocation.…”

Curcumin induces apoptosis in human lung adenocarcinoma A549 cells through a reactive oxygen species-dependent mitochondrial signaling pathway

“…Activation of these kinases causes variable cellular responses depending upon cell type. Some studies have shown that curcumin represses or promotes ERK, JNK and p38 activation, while others have found no effect of curcumin on ERK, JNK and p38 activation (13)(14)(15)(30)(31)(32). These findings indicated a dual role for MAPK in the cellular response that appeared to be specific to the type of cell and apoptotic stimulus studied.…”

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

“…Recently, it has been demonstrated that PAX3/FKHR can interact with and mediate destabilization of the transcription factor EGR1 ( (Roeb et al, 2007) and Supplementary Figures S3a and b) which itself can directly modulate gene expression of p21 ( (Choi et al, 2008;Ragione et al, 2003) and Supplementary Figure S3c)). These findings suggest that repression of p21 by PAX3/FKHR might be mediated by degradation of the transcription factor EGR1.…”