Zhao Yuanyuan, Tao Jiahao, Chen Zhuangzhong, Li Suihui, Liu Zeyu, Lin Lizhu, Zhai Linzhu
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China.
Cancer Center, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China.
PeerJ. 2021 Oct 26;9:e12339. doi: 10.7717/peerj.12339. eCollection 2021.
The anti-tumor properties of curcumin have been demonstrated for many types of cancer. However, a systematic functional and biological analysis of its target proteins has yet to be fully documented. The aim of this study was to explore the underlying mechanisms of curcumin and broaden the perspective of targeted therapies.
Direct protein targets (DPTs) of curcumin were searched in the DrugBank database. Using the STRING database, the interactions between curcumin and DPTs and indirect protein targets (IPTs) weres documented. The protein-protein interaction (PPI) network of curcumin-mediated proteins was visualized using Cytoscape. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed for all curcumin-mediated proteins. Furthermore, the cancer targets were searched in the Comparative Toxicogenomics Database (CTD). The overlapping targets were studied using Kaplan-Meier analysis to evaluate cancer survival. Further genomic analysis of overlapping genes was conducted using the cBioPortal database. Lastly, MTT, quantitative polymerase chain reaction (qPCR), and western blot (WB) analysis were used to validate the predicted results on hepatocellular carcinoma (HCC) cells.
A total of five DPTs and 199 IPTs were found. These protein targets were found in 121 molecular pathways analyzed KEGG enrichment. Based on the anti-tumor properties of curcumin, two pathways were selected, including pathways in cancer (36 genes) and HCC (22 genes). Overlapping with 505 HCC-related gene sets identified in CTD, five genes (TP53, RB1, TGFB1, GSTP1, and GSTM1) were finally identified. High mRNA levels of TP53, RB1, and GSTM1 indicated a prolonged overall survival (OS) in HCC, whereas elevated mRNA levels of TGFB1 were correlated with poor prognosis. The viability of both HepG2 cells and Hep3B cells was significantly reduced by curcumin at concentrations of 20 or 30 μM after 48 or 72 h of culture. At a concentration of 20 μM curcumin cultured for 48 h, the expression of TGFB1 and GSTP1 in Hep3B cells was reduced significantly in qPCR analysis, and reduced TGFB1 protein expression was also found in Hep3B cells.
姜黄素的抗肿瘤特性已在多种癌症类型中得到证实。然而，对其靶蛋白进行系统的功能和生物学分析尚未得到充分记录。本研究的目的是探索姜黄素的潜在作用机制，并拓宽靶向治疗的视野。
在药物银行数据库中搜索姜黄素的直接蛋白靶点（DPT）。使用STRING数据库记录姜黄素与DPT和间接蛋白靶点（IPT）之间的相互作用。使用Cytoscape可视化姜黄素介导蛋白的蛋白质-蛋白质相互作用（PPI）网络。对所有姜黄素介导的蛋白进行京都基因与基因组百科全书（KEGG）通路富集分析。此外，在比较毒理基因组学数据库（CTD）中搜索癌症靶点。使用Kaplan-Meier分析研究重叠靶点以评估癌症存活率。使用cBioPortal数据库对重叠基因进行进一步的基因组分析。最后，使用MTT、定量聚合酶链反应（qPCR）和蛋白质免疫印迹（WB）分析来验证对肝癌（HCC）细胞的预测结果。
共发现5个DPT和199个IPT。这些蛋白靶点存在于KEGG富集分析的121条分子通路中。基于姜黄素的抗肿瘤特性，选择了两条通路，包括癌症通路（36个基因）和肝癌通路（22个基因）。与CTD中鉴定的505个肝癌相关基因集重叠，最终鉴定出5个基因（TP53、RB1、TGFB1、GSTP1和GSTM1）。TP53、RB1和GSTM1的高mRNA水平表明肝癌患者的总生存期（OS）延长，而TGFB1的mRNA水平升高与预后不良相关。在培养48或72小时后，20或30μM浓度的姜黄素显著降低了HepG2细胞和Hep3B细胞的活力。在2
