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Selenium Regulates Cyclooxygenase-2 and Extracellular Signal-Regulated Kinase Signaling Pathways by Activating AMP-Activated Protein Kinase in Colon Cancer Cells

¹ Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species, Kyung Hee University College of Medicine; ² Department of Biochemistry and Molecular Toxicology, College of Pharmacy, Seoul National University, Seoul, South Korea; Departments of ³ Biological Science and ⁴ Food and Nutrition, Hannam University; and ⁵ Department of Biochemistry, Eulji University, School of Medicine, Daejeon, South Korea

Requests for reprints: Ock Jin Park, Department of Food and Nutrition, Hannam University, Daejeon 306-791, Korea. Phone: 82-42-629-7493; E-mail: ojpark{at}hannam.ac.kr or Joohun Ha, Department of Biochemistry and Molecular Biology, Kyung Hee University College of Medicine, Seoul 130-701, Korea. Phone: 82-2-961-0921; E-mail: hajh{at}khu.ac.kr.

Epidemiologic and experimental evidences indicate that selenium, an essential trace element, can reduce the risk of a variety of cancers. Protection against certain types of cancers, particularly colorectal cancers, is closely associated with pathways involving cyclooxygenase-2 (COX-2). We found that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, mediates critical anticancer effects of selenium via a COX-2/prostaglandin E₂ signaling pathway. Selenium activated AMPK in tumor xenografts as well as in colon cancer cell lines, and this activation seemed to be essential to the decrease in COX-2 expressions. Transduction with dominant-negative AMPK into colon cancer cells or application of cox-2^–/–-negative cells supported the evidence that AMPK is an upstream signal of COX-2 and inhibits cell proliferation. In HT-29 colon cancer cells, carcinogenic agent 12-O-tetradecanoylphorbol-13-acetate (TPA) activated extracellular signal-regulated kinase (ERK) that led to COX-2 expression and selenium blocked the TPA-induced ERK and COX-2 activation via AMPK. We also showed the role of a reactive oxygen species as an AMPK activation signal in selenium-treated cells. We propose that AMPK is a novel and critical regulatory component in selenium-induced cancer cell death, further implying AMPK as a prime target of tumorigenesis. (Cancer Res 2006; 66(20): 10057-63)

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