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Cyclooxygenase Inhibitors Regulate the Expression of a TGF-β Superfamily Member That Has Proapoptotic and Antitumorigenic Activities

 Seung Joon Baek  ;  Kyung-Su Kim  ;  Jennifer B. Nixon  ;  Leigh C. Wilson  ;  Thomas E. Eling 
 MOLECULAR PHARMACOLOGY, Vol.59(4) : 901-908, 2001 
Journal Title
Issue Date
Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology* ; Apoptosis* ; Cell Division/drug effects ; Colorectal Neoplasms/metabolism* ; Cyclooxygenase Inhibitors/pharmacology* ; Cytokines/biosynthesis* ; Cytokines/genetics ; Cytokines/pharmacology* ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Neoplastic/drug effects* ; Growth Differentiation Factor 15 ; Humans ; Male ; Mice ; Mice, Nude ; Molecular Sequence Data ; RNA, Messenger/metabolism ; Transfection ; Transforming Growth Factor beta/genetics ; Tumor Cells, Cultured ; Tumor Stem Cell Assay ; Xenograft Model Antitumor Assays
The antitumorigenic activity of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase (COX) inhibitors, is well established, but responsible molecular mechanisms are not fully understood. NSAIDs stimulate apoptosis by COX dependent and independent mechanisms in colorectal cells in culture. Identification of genes regulated by COX inhibitors could lead to a better understanding of their proapoptotic and anti-neoplastic activities. Using subtractive hybridization, a cDNA which was designated as NSAID activated gene (NAG-1) was identified from NSAID-treated HCT-116, human colorectal cells. NAG-1 has an identical sequence with a novel member of the TGF-beta superfamily that has 5 different names. In the HCT-116 cells, NAG-1 expression is increased and apoptosis is induced by treatment with some NSAIDs in a concentration and time-dependent manner. NAG-1 transfected cells exhibited increased basal apoptosis, increased response to NSAIDs and reduced soft agar cloning efficiency. Furthermore, transplantable tumors derived from NAG-1 transfected HCT-116 cells showed reduced tumorigenicity in athymic nude mice compared with vector-transfected HCT-116 cells. The increased NAG-1 expression by NSAIDs provides a suitable explanation for COX-independent apoptotic effects of NSAIDs in cultured cells. These data demonstrate that NAG-1 is an antitumorigenic and proapoptotic protein, and its regulation by COX inhibitors may provide new clues for explaining their proapoptotic and antitumorigenic activities.
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1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Su(김경수) ORCID logo https://orcid.org/0000-0003-1460-0640
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