Resveratrol Inhibits Pancreatic Cancer Cell Proliferation Through Transcriptional Induction of Macrophage Inhibitory Cytokine-1

• Published in: The Journal of surgical research 2007-04, Vol.138 (2), p.163-169
• Main Authors: Golkar, Laleh, M.D, Ding, Xian-Zhong, M.D., Ph.D, Ujiki, Michael B., M.D, Salabat, Mohammad R., M.D, Kelly, David L., Ph.D, Scholtens, Denise, Ph.D, Fought, Angela J., M.S, Bentrem, David J., M.D, Talamonti, Mark S., M.D, Bell, Richard H., M.D, Adrian, Thomas E., Ph.D
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; Bone Morphogenetic Proteins - genetics; Cell Division - drug effects; Cell Line, Tumor; Dactinomycin - pharmacology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic - drug effects; General aspects; Growth Differentiation Factor 15; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; macrophage inhibitory cytokine-1(MIC-1); Medical sciences; Nucleic Acid Synthesis Inhibitors - pharmacology; Oligonucleotide Array Sequence Analysis; pancreatic cancer; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - physiopathology; Resveratrol; RNA, Small Interfering; Stilbenes - pharmacology; Surgery; Transcription, Genetic - drug effects; Transfection; Tumors; Up-Regulation - drug effects
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2006.05.037

Introduction Resveratrol is a phenolic compound found in grape skins, mulberries, and certain nuts that has been shown to have antitumorigenic and anti-inflammatory properties. Macrophage inhibitory cytokine (MIC-1) is a member of the transforming growth factor beta (TGF-β) superfamily that has been shown to have antitumorigenic activity and is up-regulated in resveratrol-treated cancer cells. Resveratrol inhibits proliferation of human pancreatic cancer cells; however, the exact mechanism of action is not known. In this study, we investigated the role of MIC-1 in resveratrol-induced growth inhibition of human pancreatic cancer cell lines. Methods and results Proliferation assays conducted with resveratrol-treated human pancreatic cancer cell lines (CD18 and S2-013) at 24, 48, and 72 h revealed inhibition of cell proliferation compared to controls. Using oligonucleotide microarray analysis, we identified marked up-regulation of MIC-1 gene expression in resveratrol-treated human pancreatic cancer S2-013 cells. Real-time RT-PCR performed in CD18 and S2-013 cells treated with resveratrol (0-100 μm) for 24 h confirmed concentration and time-dependent up-regulation of expression of one particular gene, MIC-1. Both cell lines pretreated with actinomycin D (a transcriptional inhibitor) and then resveratrol had reduced up-regulation of MIC-1 gene expression compared to those treated with resveratrol alone. Finally, resveratrol-induced growth inhibition was abolished in CD18 cells transfected with MIC-1 short interfering RNA. Conclusions Resveratrol up-regulates MIC-1 gene expression in part at the transcriptional level in pancreatic cancer cells. Furthermore, MIC-1 appears to play a key role in resveratrol-induced growth inhibition in these cells.