Resveratrol inhibits pancreatic cancer cell proliferation through transcriptional induction of macrophage inhibitory cytokine-1.
BACKGROUND
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-beta) 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.


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 mum) 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.
Golkar
Laleh
L
Department of Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
Ding
Xian-Zhong
XZ
Ujiki
Michael B
MB
Salabat
Mohammad R
MR
Kelly
David L
DL
Scholtens
Denise
D
Fought
Angela J
AJ
Bentrem
David J
DJ
Talamonti
Mark S
MS
Bell
Richard H
RH
Adrian
Thomas E
TE
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055436:Growth Differentiation Factor 15; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D034741:RNA, Small Interfering; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D019485:Bone Morphogenetic Proteins; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D019384:Nucleic Acid Synthesis Inhibitors; D034741:RNA, Small Interfering; D013267:Stilbenes; D003609:Dactinomycin; D000077185:Resveratrol