Full Text:   <1180>

Summary:  <342>

Suppl. Mater.: 

CLC number: 

On-line Access: 2022-08-12

Received: 2022-01-22

Revision Accepted: 2022-04-27

Crosschecked: 2022-08-12

Cited: 0

Clicked: 1886

Citations:  Bibtex RefMan EndNote GB/T7714




Dongyan GUO


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2022 Vol.23 No.8 P.682-698


Investigation and experimental validation of curcumin-related mechanisms against hepatocellular carcinoma based on network pharmacology

Author(s):  Yang CHEN, Qian LI, Sisi REN, Ting CHEN, Bingtao ZHAI, Jiangxue CHENG, Xiaoyan SHI, Liang SONG, Yu FAN, Dongyan GUO

Affiliation(s):  College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, China; more

Corresponding email(s):   2111006@sntcm.edu.cn, xmc2051080@163.com

Key Words:  Curcumin, Network pharmacology, p53, Adenosine 5'-monophosphate (AMP)‍, -activated protein kinase (AMPK), Apoptosis, Autophagy

Yang CHEN, Qian LI, Sisi REN, Ting CHEN, Bingtao ZHAI, Jiangxue CHENG, Xiaoyan SHI, Liang SONG, Yu FAN, Dongyan GUO. Investigation and experimental validation of curcumin-related mechanisms against hepatocellular carcinoma based on network pharmacology[J]. Journal of Zhejiang University Science B, 2022, 23(8): 682-698.

@article{title="Investigation and experimental validation of curcumin-related mechanisms against hepatocellular carcinoma based on network pharmacology",
author="Yang CHEN, Qian LI, Sisi REN, Ting CHEN, Bingtao ZHAI, Jiangxue CHENG, Xiaoyan SHI, Liang SONG, Yu FAN, Dongyan GUO",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Investigation and experimental validation of curcumin-related mechanisms against hepatocellular carcinoma based on network pharmacology
%A Yang CHEN
%A Qian LI
%A Sisi REN
%A Ting CHEN
%A Bingtao ZHAI
%A Jiangxue CHENG
%A Xiaoyan SHI
%A Liang SONG
%A Dongyan GUO
%J Journal of Zhejiang University SCIENCE B
%V 23
%N 8
%P 682-698
%@ 1673-1581
%D 2022
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200038

T1 - Investigation and experimental validation of curcumin-related mechanisms against hepatocellular carcinoma based on network pharmacology
A1 - Yang CHEN
A1 - Qian LI
A1 - Sisi REN
A1 - Ting CHEN
A1 - Bingtao ZHAI
A1 - Jiangxue CHENG
A1 - Xiaoyan SHI
A1 - Liang SONG
A1 - Yu FAN
A1 - Dongyan GUO
J0 - Journal of Zhejiang University Science B
VL - 23
IS - 8
SP - 682
EP - 698
%@ 1673-1581
Y1 - 2022
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200038

ObjectiveTo determine the potential molecular mechanisms underlying the therapeutic effect of curcumin on hepatocellular carcinoma (HCC) by network pharmacology and experimental in vitro validation.
MethodsThe predictive targets of curcumin or HCC were collected from several databases. the identified overlapping targets were crossed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) platform. Two of the candidate pathways were selected to conduct an experimental verification. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium (MTT) assay was used to determine the effect of curcumin on the viability of HepG2 and LO2 cells. The apoptosis and autophagy of HepG2 cells were respectively detected by flow cytometry and transmission electron microscopy. Besides, western blot and real-time polymerase chain reaction (PCR) were employed to verify the p53 apoptotic pathway and adenosine 5'-monophosphate (AMP)‍;-activated protein kinase (AMPK) autophagy pathway. HepG2 cells were pretreated with pifithrin-‍α(PFT-‍α) and GSK690693 for further investigation.
ResultsThe 167 pathways analyzed by KEGG included apoptosis, autophagy, p53, and AMPK pathways. The GO enrichment analysis demonstrated that curcumin was involved in cellular response to drug, regulation of apoptotic pathway, and so on. The in vitro experiments also confirmed that curcumin can inhibit the growth of HepG2 cells by promoting the apoptosis of p53 pathway and autophagy through the AMPK pathway. Furthermore, the protein and messenger RNA (mRNA) of the two pathways were downregulated in the inhibitor-pretreated group compared with the experimental group. The damage-regulated autophagy modulator (DRAM) in the PFT-‍α-pretreated group was downregulated, and p62 in the GSK690693-pretreated group was upregulated.
Conclusionscurcumin can treat HCC through the p53 apoptotic pathway and the AMPK/Unc-51-like kinase 1 (ULK1) autophagy pathway, in which the mutual transformation of autophagy and apoptosis may occur through DRAM and p62.


方法:从多个数据库收集姜黄素作用和肝癌治疗潜在靶点,利用DAVID平台将交集靶点进行GO和KEGG分析,预测姜黄素防治肝癌的相关信号通路。结合预测结果,采用MTT法检测姜黄素对HepG2和LO2细胞活力的影响;运用流式细胞术和透射电镜检测姜黄素处理后,HepG2细胞的凋亡和自噬情况;并经western blot和real-time PCR验证p53凋亡及AMPK自噬通路在姜黄素治疗肝癌中的作用。最后,通过p53抑制剂pifithrin-α和AMPK抑制剂GSK690693的使用进一步探索姜黄素治疗肝癌潜在的分子机制。


Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]AilioaieLM, LitscherG, 2020. Curcumin and photobiomodulation in chronic viral hepatitis and hepatocellular carcinoma. Int J Mol Sci, 21(19):7150.

[2]AmbergerJS, BocchiniCA, ScottAF, et al., 2019. OMIM.org: leveraging knowledge across phenotype-gene relationships. Nucleic Acids Res, 47(D1):D1038-D1043.

[3]BaiZS, PengYL, YeXY, et al., 2022. Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 23(2):89-101.

[4]BrarG, GretenTF, GraubardBI, et al., 2020. Hepatocellular carcinoma survival by etiology: a SEER-Medicare database analysis. Hepatol Commun, 4(10):1541-1551.

[5]ChenN, DebnathJ, 2010. Autophagy and tumorigenesis. FEBS Lett, 584(7):1427-1435.

[6]ChiablaemK, LirdprapamongkolK, KeeratichamroenS, et al., 2014. Curcumin suppresses vasculogenic mimicry capacity of hepatocellular carcinoma cells through STAT3 and PI3K/AKT inhibition. Anticancer Res, 34(4):‍1857-1864.

[7]CrightonD, WilkinsonS, O'PreyJ, et al., 2006. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell, 126(1):121-134.

[8]CrightonD, WilkinsonS, RyanKM, 2007. DRAM links autophagy to p53 and programmed cell death. Autophagy, 3(1):72-74.

[9]D'ArcyMS, 2019. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int, 43(6):582-592.

[10]DainaA, MichielinO, ZoeteV, 2019. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res, 47(W1):W357-W364.

[11]DarveshAS, AggarwalBB, BishayeeA, 2012. Curcumin and liver cancer: a review. Curr Pharm Biotechnol, 13(1):218-228.

[12]DavisAP, GrondinCJ, JohnsonRJ, et al., 2019. The comparative toxicogenomics database: update 2019. Nucleic Acids Res, 47(D1):D948-D954.

[13]DonadonV, BalbiM, MasMD, et al., 2010. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int, 30(5):750-758.

[14]FanTJ, SunGH, SunXD, et al., 2019. Tumor energy metabolism and potential of 3-bromopyruvate as an inhibitor of aerobic glycolysis: implications in tumor treatment. Cancers (Basel), 11(3):317.

[15]FishilevichS, NudelR, RappaportN, et al., 2017. Genehancer: genome-wide integration of enhancers and target genes in GeneCards. Database (Oxford), 2017:bax028.

[16]GfellerD, MichielinO, ZoeteV, 2013. Shaping the interaction landscape of bioactive molecules. Bioinformatics, 29(23):3073-3079.

[17]GlickD, BarthS, MacleodKF, 2010. Autophagy: cellular and molecular mechanisms. J Pathol, 221(1):3-12.

[18]HardieDG, AlessiDR, 2013. LKB1 and AMPK and the cancer-metabolism link - ten years after. BMC Biol, 11:36.

[19]HeZ, LiuH, AgostiniM, et al., 2013. p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene. Cell Death Differ, 20(10):1415-1424.

[20]HopkinsAL, 2007. Network pharmacology. Nat Biotechnol, 25(10):1110-1111.

[21]IslamA, SooroMA, ZhangPH, 2018. Autophagic regulation of p62 is critical for cancer therapy. Int J Mol Sci, 19(5):1405.

[22]JiangLH, CaiXL, LiS, et al., 2021. Hydroxyethyl starch curcumin enhances antiproliferative effect of curcumin against HepG2 cells via apoptosis and autophagy induction. Front Pharmacol, 12:755054.

[23]JinZY, LiY, PittiR, et al., 2009. Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell, 137(4):‍721-735.

[24]JingKP, SongKS, ShinS, et al., 2011. Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53. Autophagy, 7(11):1348-1358.

[25]JulienO, WellsJA, 2017. Caspases and their substrates. Cell Death Differ, 24(8):1380-1389.

[26]KatsuragiY, IchimuraY, KomatsuM, 2015. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J, 282(24):4672-4678.

[27]LamarkT, SvenningS, JohansenT, 2017. Regulation of selective autophagy: the p62/SQSTM1 paradigm. Essays Biochem, 61(6):609-624.

[28]LeeSH, ChoWJ, NajyAJ, et al., 2021. P62/SQSTM1-induced caspase-8 aggresomes are essential for ionizing radiation-mediated apoptosis. Cell Death Dis, 12(11):997.

[29]LiM, ZhangW, WangB, et al., 2016. Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma. Int J Nanomedicine, 11:5645-5669.

[30]LiYJ, ChenYY, 2019. AMPK and autophagy. In: Qin ZH (Ed.), Autophagy: Biology and Diseases. Springer, Singapore, p.85-108.

[31]LiangCY, JungJU, 2010. Autophagy genes as tumor suppressors. Curr Opin Cell Biol, 22(2):226-233. https://doi.org10.1016/j.ceb.2009.11.003

[32]LibertiMV, LocasaleJW, 2016. The Warburg Effect: how does it benefit cancer cells? Trends Biochem Sci, 41(3):211-218.

[33]LiuWH, ZhangZB, LinGS, et al., 2017. Tetrahydrocurcumin is more effective than curcumin in inducing the apoptosis of H22 cells via regulation of a mitochondrial apoptosis pathway in ascites tumor-bearing mice. Food Funct, 8(9):3120-3129.

[34]LiuX, LiuJK, 2020. Tanshinone I induces cell apoptosis by reactive oxygen species-mediated endoplasmic reticulum stress and by suppressing p53/DRAM-mediated autophagy in human hepatocellular carcinoma. Artif Cells Nanomed Biotechnol, 48(1):488-497.

[35]MaiuriMC, ZalckvarE, KimchiA, et al., 2007. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol, 8(9):741-752.

[36]MariñoG, Niso-SantanoM, BaehreckeEH, et al., 2014. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol, 15(2):81-94.

[37]MoscatJ, Diaz-MecoMT, 2009. p62 at the crossroads of autophagy, apoptosis, and cancer. Cell, 137(6):1001-1004.

[38]OnoratiAV, DyczynskiM, OjhaR, et al., 2018. Targeting autophagy in cancer. Cancer, 124(16):3307-3318.

[39]PiñeroJ, Ramírez-AnguitaJM, Saüch-PitarchJ, et al., 2020. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res, 48(D1):D845-D855.

[40]QuanWY, LeeMS, 2013. Role of autophagy in the control of body metabolism. Endocrinol Metab, 28(1):6-11.

[41]RahibL, SmithBD, AizenbergR, et al., 2014. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res, 74(11):2913-2921.

[42]TsaprasP, NezisIP, 2017. Caspase involvement in autophagy. Cell Death Differ, 24(8):1369-1379.

[43]Vander HeidenMG, CantleyLC, ThompsonCB, 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324(5930):1029-1033.

[44]WangFL, YeX, ZhaiDD, et al., 2020. Curcumin-loaded nanostructured lipid carrier induced apoptosis in human HepG2 cells through activation of the DR5/caspase-mediated extrinsic apoptosis pathway. Acta Pharm, 70(2):227-237.

[45]WangKW, 2015. Autophagy and apoptosis in liver injury. Cell Cycle, 14(11):1631-1642.

[46]WangYX, ZhangS, LiFC, et al., 2020. Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics. Nucleic Acids Res, 48(D1):D1031-D1041.

[47]WhiteE, 2016. Autophagy and p53. Cold Spring Harb Perspect Med, 6(4):a026120.

[48]WishartDS, FeunangYD, GuoAC, et al., 2018. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res, 46(D1):D1074-D1082.

[49]XuHY, ZhangYQ, LiuZM, et al., 2019. ETCM: an encyclopaedia of traditional Chinese medicine. Nucleic Acids Res, 47(D1):D976-D982.

[50]XuMX, ZhaoLL, DengCY, et al., 2013. Curcumin suppresses proliferation and induces apoptosis of human hepatocellular carcinoma cells via the wnt signaling pathway. Int J Oncol, 43(6):1951-1959.

[51]XueRC, FangZ, ZhangMX, et al., 2013. TCMID: traditional Chinese medicine integrative database for herb molecular mechanism analysis. Nucleic Acids Res, 41(D1):D1089-D1095.

[52]ZhangRZ, ZhuX, BaiH, et al., 2019. Network pharmacology databases for traditional Chinese medicine: review and assessment. Front Pharmacol, 10:123.

[53]ZhaoY, ZhuQ, BuXM, et al., 2020. Triggering apoptosis by oroxylin a through caspase-8 activation and p62/SQSTM1 proteolysis. Redox Biol, 29:101392.

[54]ZhengLY, YangW, WuFQ, et al., 2013. Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clin Cancer Res, 19(19):5372-5380.

[55]ZhouCG, HuC, WangB, et al., 2020. Curcumin suppresses cell proliferation, migration, and invasion through modulating miR-21-5p/SOX6 axis in hepatocellular carcinoma. Cancer Biother Radiopharm, ahead of print.

[56]ZhuW, ZhouBL, RongLJ, et al., 2020. Roles of PTBP1 in alternative splicing, glycolysis, and oncogensis. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(2):122-136.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE