姜黄素通过下调ADAMTS18基因甲基化作用于NF-kB和AKT信号通路抑制肾癌发生发展的机制研究

Ben XU; Yi-ji PENG; Wei-jie ZHU

doi:10.1007/s11655-021-3445-z

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姜黄素通过下调ADAMTS18基因甲基化作用于NF-kB和AKT信号通路抑制肾癌发生发展的机制研究

Original Article | Updated：2022-06-27

- 姜黄素通过下调ADAMTS18基因甲基化作用于NF-kB和AKT信号通路抑制肾癌发生发展的机制研究
- Curcumin Inhibits Viability of Clear Cell Renal Cell Carcinoma by Down-Regulating ADAMTS18 Gene Methylation through NF-κB and AKT Signaling Pathway
- Chinese Journal of Integrative Medicine 2022年28卷第5期页码：419-424
- Affiliations：
  
  Department of Urology, Peking University First Hospital and Institute of Urology, Peking University, National Urological Cancer Center, Beijing (100034), China
- Author bio：
  
  Dr. XU Ben, E-mail: xuben_pku@sina.com
- Funds：
  
  the Beijing Natural Science Foundation(7204316);Beijing Traditional Chinese Medicine Development Fundation(QN-2020-03);Peking University Medicine Fund of Fostering Young Scholars' Scientific & Technological Innovation(BMU2020PYB018)
- DOI：10.1007/s11655-021-3445-z
  中图分类号：
- 纸质出版日期：2022-05-01，
  
  网络出版日期：2021-05-17，
  
  录用日期：2021-02-07
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Ben XU, Yi-ji PENG, Wei-jie ZHU. 姜黄素通过下调ADAMTS18基因甲基化作用于NF-kB和AKT信号通路抑制肾癌发生发展的机制研究[J]. Chinese Journal of Integrative Medicine, 2022,28(5):419-424.

Ben XU, Yi-ji PENG, Wei-jie ZHU. Curcumin Inhibits Viability of Clear Cell Renal Cell Carcinoma by Down-Regulating ADAMTS18 Gene Methylation through NF-κB and AKT Signaling Pathway[J]. Chinese Journal of Integrative Medicine, 2022,28(5):419-424.
Ben XU, Yi-ji PENG, Wei-jie ZHU. 姜黄素通过下调ADAMTS18基因甲基化作用于NF-kB和AKT信号通路抑制肾癌发生发展的机制研究[J]. Chinese Journal of Integrative Medicine, 2022,28(5):419-424. DOI： 10.1007/s11655-021-3445-z.

Ben XU, Yi-ji PENG, Wei-jie ZHU. Curcumin Inhibits Viability of Clear Cell Renal Cell Carcinoma by Down-Regulating ADAMTS18 Gene Methylation through NF-κB and AKT Signaling Pathway[J]. Chinese Journal of Integrative Medicine, 2022,28(5):419-424. DOI： 10.1007/s11655-021-3445-z.

摘要

目的:

本文通过探讨姜黄素对肾癌细胞增殖、分裂周期及凋亡的影响

并分析姜黄素影响肾癌发生发展可能的分子机制.

方法:

采用MTT法在24、48、72小时分别分析1.25、2.5、5、10μmol/L姜黄素对肾癌细胞系A498和786-0增殖能力的影响; WB法测定10μmol/L姜黄素处理前后ADAMTS18基因、p65、磷酸化p65 (pp65) 、AKT、磷酸化AKT (pAKT) 和MMP2的表达. Real-time PCR和甲基化特异性PCR (MSP) 分别用来测定10μmol/L姜黄素处理前后ADAMTS18基因的表达与甲基化水平.

结果:

姜黄素能显著抑制肾癌细胞A498和786-0的活性

并且具有剂量和时间依赖性 (

0.01) ; 姜黄素处理后

ADAMTS18基因表达上调伴甲基化水平下降

同时NF-kB通路蛋白 (p65、pp65) 、AKT通路蛋白 (AKT、pAKT) 和两条通路共同蛋白MMP2的表达水平均下降. 过表达ADAMTS18基因时

p65、AKT和MMP2的表达下降

而当沉默ADAMTS18基因时

三者的表达水平反而上调

采用NF-κB抑制剂PDTC及AKT抑制剂LY294002处理后

三者的表达水平下调.

结论:

姜黄素通过下调ADAMTS18基因甲基化作用于NF-kB和AKT信号通路

进而可以抑制肾癌的发生发展过程.

Abstract

Objective:

To investigate the effect of curcumin on viability of clear cell renal cell carcinoma (ccRCC) and analyze its possible mechanism.

Methods:

In cell lines of A498 and 786-O

the effects of curcumin (1.25

2.5

5 and 10 μmol/L) on the viability of ccRCC were analyzed at 24

48 and 72 h by MTT assay. The protein expression levels of ADAMTS18 gene

p65

phosphorylation p65 (pp65)

AKT

phosphorylation AKT (pAKT) and matrix metallopeptidase 2 (MMP-2) before and after curcumin (10 μmol/L) treatment were examined by Western blotting. Real-time PCR and methylation specific PCR (MSP) were applied to analyze the expression and methylation level of ADAMTS18 gene before and after curcumin treatment (10 μmol/L).

Results:

Curcumin significantly inhibited the viability of A498 and 786-O cell lines in a dose- and time-dependent manner (

0.01). Up-regulation of ADAMTS18 gene expression with down-regulation of ADAMTS18 gene methylation was reflected after curcumin treatment

accompanied by down-regulation of nuclear factor κB (NF-κkB) related protein (p65 and pp65)

AKT related protein (AKT and pAKT)

and NF-κB/AKT common related protein MMP-2. With ADAMTS18 gene overexpressed

the expression levels of p65

AKT and MMP2 were downregulated

of which were conversely up-regulated in silenced ADAMTS18 (sh-ADAMTS18). The expression of pp65

pAKT and MMP2 in sh-ADAMTS18 was down-regulated after being treated with PDTC (NF-κB inhibitor) and LY294002 (AKT inhibitor).

Conclusion:

Curcumin could inhibit the viability of ccRCC by down-regulating ADAMTS18 gene methylation though NF-κB and AKT signaling pathway.

关键词

Keywords

curcuminclear cell renal cell carcinomaADAMTS18 genemethylationsignaling pathway

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