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p21^Waf1/Cip1 Expression by Curcumin in U-87MG Human Glioma Cells: Role of Early Growth Response-1 Expression

¹ Department of Biomedical Science and Technology, Research Center for Transcription Control, Institute of Biomedical Science and Technology, and ² Division of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, Korea; ³ Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Ansan, Korea; and ⁴ Department of Biochemistry, College of Natural Science, Kyungpook National University, Daegu, Korea

Requests for reprints: Young Han Lee and Soon Young Shin, Department of Biomedical Science and Technology, Research Center for Transcription Control, Institute of Biomedical Science and Technology, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, South Korea. Phone: 82-2-2049-6115; Fax: 82-2-3437-9781; E-mail: yhlee58{at}konkuk.ac.kr and syshin{at}hanyang.ac.kr.

Key Words: curcumin • Egr-1 • p21

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 p21^Waf1/Cip1. Both p53-dependent and p53-independent mechanisms regulate p21^Waf1/Cip1 expression, but the mechanism by which curcumin regulates p21^Waf1/Cip1 expression remains unknown. Here, we report that transcription of the p21^Waf1/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 NH₂-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]

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