title: Sirt1 Is Required for Resveratrol-Mediated Chemopreventive Effects in Colorectal Cancer Cells.
abstract: Sirt1 is a NAD⁺-dependent protein-modifying enzyme involved in regulating gene expression, DNA damage repair, metabolism and survival, as well as acts as an important subcellular target of resveratrol. The complex mechanisms underlying Sirt1 signaling during carcinogenesis remain controversial, as it can serve both as a tumor promoter and suppressor. Whether resveratrol-mediated chemopreventive effects are mediated via Sirt1 in CRC growth and metastasis remains unclear; which was the subject of this study. We found that resveratrol suppressed proliferation and invasion of two different human CRC cells in a dose-dependent manner, and interestingly, this was accompanied with a significant decrease in Ki-67 expression. By transient transfection of CRC cells with Sirt1-ASO, we demonstrated that the anti-tumor effects of resveratrol on cells was abolished, suggesting the essential role of this enzyme in the resveratrol signaling pathway. Moreover, resveratrol downregulated nuclear localization of NF-κB, NF-κB phosphorylation and its acetylation, causing attenuation of NF-κB-regulated gene products (MMP-9, CXCR4) involved in tumor-invasion and metastasis. Finally, Sirt1 was found to interact directly with NF-κB, and resveratrol did not suppress Sirt1-ASO-induced NF-κB phosphorylation, acetylation and NF-κB-regulated gene products. Overall, our results demonstrate that resveratrol can suppress tumorigenesis, at least in part by targeting Sirt1 and suppression of NF-κB activation.
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, Munich D-80336, Germany. constanze.buhrmann@med.uni-muenchen.de.
authors.forename: Constanze
authors.initials: C
authors.lastname: Buhrmann
authors.affiliation: Department of Parasitology, Faculty of Veterinary Medicine, University of Tehran, Tehran 141556453, Iran. pshayan@ut.ac.ir.|Investigating Institute of Molecular Biological System Transfer, Tehran 1417863171, Iran. pshayan@ut.ac.ir.
authors.forename: Parviz
authors.initials: P
authors.lastname: Shayan
authors.affiliation: Department of Anatomy and Cell Biology, Biomedical Center, Ludwig-Maximilian-University Munich, Martinsried D-82152, Germany. Bastian.Popper@med.uni-muenchen.de.
authors.forename: Bastian
authors.initials: B
authors.lastname: Popper
authors.affiliation: Center for Gastrointestinal Research; Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA. AjayG@BaylorHealth.edu.
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, Munich D-80336, Germany. mehdi.shakibaei@med.uni-muenchen.de.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C527276:CXCR4 protein, human; D019394:Ki-67 Antigen; D016376:Oligonucleotides, Antisense; C498143:RELA protein, human; D019718:Receptors, CXCR4; D013267:Stilbenes; D051996:Transcription Factor RelA; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: NF-κB; Sirt1; alginate; carcinogenesis; human colon cancer; resveratrol