The conventional nonsteroidal anti-inflammatory drug sulindac sulfide arrests ovarian cancer cell growth via the expression of NAG-1/MIC-1/GDF-15.
Although the chemopreventive and antitumorigenic activities of nonsteroidal anti-inflammatory drug (NSAID) against colorectal cancer are well established, the molecular mechanisms responsible for these properties in ovarian cancer have not been elucidated. Therefore, there is an urgent need to develop mechanism-based approaches for the management of ovarian cancer. To this end, the effect of several NSAIDs on ovarian cancer cells was investigated as assessed by the induction of NAG-1/MIC-1/GDF-15, a proapoptotic gene belonging to the transforming growth factor-beta superfamily. Sulindac sulfide was the most significant NSAID activated gene 1 (NAG-1) inducer and its expression was inversely associated with cell viability as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. This growth suppression by sulindac sulfide was recovered by transfection of NAG-1 small interfering RNA. These results indicate that NAG-1 is one of the genes responsible for growth suppression by sulindac sulfide. Furthermore, we observed down-regulation of p21 WAF1/CIP1 by introduction of NAG-1 small interfering RNA into sulindac sulfide-treated cells. In addition, to elucidate other potential molecular mechanisms involved in sulindac sulfide treatment of ovarian cancer cells, we did a membrane-based microarray experiment. We found that cyclin D1, MMP-1, PI3KR1, and uPA were down-regulated by sulindac sulfide. In conclusion, a novel molecular mechanism is proposed to explain the experimental results and provide a rationale for the chemopreventive activity of NSAIDs in ovarian cancer.
Kim
Jong-Sik
JS
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, MD: E4-09, P.O. Box 12233, 111 TW Alexander Drive, Research Triangle Park, NC 27709, USA.
Baek
Seung Joon
SJ
Sali
Tina
T
Eling
Thomas E
TE
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D055436:Growth Differentiation Factor 15; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D004396:Coloring Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D034741:RNA, Small Interfering; D013778:Tetrazolium Salts; D013844:Thiazoles; D019938:Cyclin D1; D013467:Sulindac; C025462:sulindac sulfide; D008156:Luciferases; C022616:thiazolyl blue