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.
Highlights
Colorectal cancer (CRC) is one of the major leading causes of tumor-associated deaths in the world, with high rates of incidence and disease-related mortality and morbidity [1]
The purpose of this paper was to investigate whether resveratrol/Sirtuin 1 (Sirt1)-mediated signaling during carcinogenesis plays a role against the growth and metastasis of CRC cells
We used two different well-characterized cell lines, microsatellite instability MSI+ (HCT116) and MSI (SW480) cells, as well as cells that are WT for p53 (HCT116) and mutant (SW480) [57], since 5-Fluorouracil (5FU)-mediated resistance is tightly linked to MSI and p53 status in CRC, derived from colorectal cancer cells, and we evaluated the effects of resveratrol on Sirt1 targeting using Sirt1-antisense oligonucleotides (ASO) on NF-κB signaling pathways in human CRC cells
Summary
Colorectal cancer (CRC) is one of the major leading causes of tumor-associated deaths in the world, with high rates of incidence and disease-related mortality and morbidity [1]. There is a growing recognition that the tumor microenvironment is very complex and contains different cell types and factors, which play a critical role during the initiation, proliferation, metastasis and maintenance of cancers [3,4,5,6]. Several reports have shown that resveratrol has inhibitory effects on various types of cancer cell lines and preclinical animal models of various cancers, such as colon, breast and lymphoma, through its activity on diverse subcellular targets, including Sirt1 [15,16,17,18,19,20,21]. Sirtuins (SIRT1 to SIRT7), the class III histone/protein deacetylases (HDACs), have been shown to regulate a variety of cellular processes involved in metabolism, differentiation, inflammation, aging, apoptosis, proliferation and cell cycle regulation. Resveratrol is a specific and potent activator of subcellular target histone deacetylase Sirt in different human tissues, including human tumors [17,33,34,35,36]
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