Lu Juanjuan, Zhang Liping, Chen Xiang, Lu Qiming, Yang Yuxia, Liu Jingping, Ma Xin
Department of Digestive Disease, Gansu Provincial Hospital 160 Donggang West Road, Lanzhou 730000, China.
Int J Clin Exp Med. 2014 Dec 15;7(12):5050-8. eCollection 2014.
Sirtuin-1 (SIRT1) possesses apparently dual roles in regulation of tumor. Previous reports have documented the crosstalk between SIRT1 with signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-B (NF-κB) signaling in leukemia, lymphoma and myeloma. In this study, the purpose was to survey the regulatory effects of SIRT1 on gastric cancer (GC) cells (AGS and MKN-45) and the relationships between SIRT1 and activation of STAT3 and NF-κB in GC cells. We found the SIRT1 activator (resveratrol RSV) contributed to the repression of viability and increase of senescence, which were rescued by SIRT1 inhibitor (nicotinamide NA) and SIRT1 depletion by CCK-8 assay and SA-β-gal assay respectively. Further study found SIRT1 activation (RSV supplement) not only inhibited the activation of STAT3 including STAT3 mRNA level, c-myc mRNA level phosphorylated STAT3 (pSTAT3) proteins and acetylizad STAT3 (acSTAT3) proteins, but also repression of pNF-κB p65 and acNF-κB p65. NA reversed the effects of RSV. In addition, either RSV or NA application could not change the cellular viability and senescence in MKN-45 cells with STAT3 knockdown or NF-κB knockdown. Overall, our findings suggested SIRT1 activation could induced the loss of viability and increases of senescence in GC in vitro. Moreover, our observations revealed SIRT1 displayed growth inhibitory activity in GC cells highly associated with causing repression of activation of STAT3 and NF-κB proteins via deacetylation.
沉默调节蛋白-1（SIRT1）在肿瘤调控中显然具有双重作用。先前的报道已记录了SIRT1与白血病、淋巴瘤和骨髓瘤中信号转导及转录激活因子3（STAT3）和核因子κB（NF-κB）信号之间的相互作用。在本研究中，目的是探究SIRT1对胃癌（GC）细胞（AGS和MKN-45）的调节作用以及SIRT1与GC细胞中STAT3和NF-κB激活之间的关系。我们发现SIRT1激活剂（白藜芦醇RSV）有助于抑制细胞活力并增加衰老，分别通过CCK-8测定法和SA-β-半乳糖苷酶测定法发现，SIRT1抑制剂（烟酰胺NA）和SIRT1缺失可挽救这些作用。进一步研究发现，SIRT1激活（补充RSV）不仅抑制STAT3的激活，包括STAT3 mRNA水平、c-myc mRNA水平、磷酸化STAT3（pSTAT3）蛋白和乙酰化STAT3（acSTAT3）蛋白，还抑制pNF-κB p65和acNF-κB p65。NA可逆转RSV的作用。此外，应用RSV或NA均不能改变STAT3或NF-κB敲低的MKN-45细胞的细胞活力和衰老。总体而言，我们的研究结果表明，SIRT1激活可在体外诱导GC细胞活力丧失和衰老增加。此外，我们的观察结果显示，SIRT1在GC细胞中表现出生长抑制活性，这与通过去乙酰化导致STAT3和NF-κB蛋白激活受抑制高度相关。
