BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Dihydroartemisinin inhibits HepG2.2.15 proliferation by inducing cellular senescence and autophagy

  • Zou, Jiang (Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College) ;
  • Ma, Qiang (Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College) ;
  • Sun, Ru (Department of Laboratory Medicine, North Sichuan Medical College) ;
  • Cai, Jiajing (Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College) ;
  • Liao, Hebin (Translational Medicine Research Center, North Sichuan Medical College) ;
  • Xu, Lei (Translational Medicine Research Center, North Sichuan Medical College) ;
  • Xia, Jingruo (Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College) ;
  • Huang, Guangcheng (Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College) ;
  • Yao, Lihua (Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College) ;
  • Cai, Yan (Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College) ;
  • Zhong, Xiaowu (Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College) ;
  • Guo, Xiaolan (Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College)
  • Received : 2019.02.24
  • Accepted : 2019.06.28
  • Published : 2019.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

Dihydroartemisinin (DHA) has been reported to possess anti-cancer activity against many cancers. However, the pharmacologic effect of DHA on HBV-positive hepatocellular carcinoma (HCC) remains unknown. Thus, the objective of the present study was to determine whether DHA could inhibit the proliferation of HepG2.2.15 cells and uncover the underlying mechanisms involved in the effect of DHA on HepG2.2.15 cells. We found that DHA effectively inhibited HepG2.2.15 HCC cell proliferation both in vivo and in vitro. DHA also reduced the migration and tumorigenicity capacity of HepG2.2.15 cells. Regarding the underlying mechanisms, results showed that DHA induced cellular senescence by up-regulating expression levels of proteins such as p-ATM, p-ATR, ${\gamma}-H_2AX$, P53, and P21 involved in DNA damage response. DHA also induced autophagy (green LC3 puncta gathered together and LC3II/LC3I ratio increased through AKT-mTOR pathway suppression). Results also revealed that DHA-induced autophagy was not linked to senescence or cell death. TPP1 (telomere shelterin) overexpression could not rescue DHA-induced anticancer activity (cell proliferation). Moreover, DHA down-regulated TPP1 expression. Gene knockdown of TPP1 caused similar phenotypes and mechanisms as DHA induced phenotypes and mechanisms in HepG2.2.15 cells. These results demonstrate that DHA might inhibit HepG2.2.15 cells proliferation through inducing cellular senescence and autophagy.

Keywords

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68, 394-424 https://doi.org/10.3322/caac.21492
  2. Mokdad AA, Lopez AD, Shahraz S et al (2014) Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med 12, 145 https://doi.org/10.1186/s12916-014-0145-y
  3. Eastman RT and Fidock DA (2009) Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nat Rev Microbiol 7, 864-874 https://doi.org/10.1038/nrmicro2239
  4. Tong Y, Liu Y, Zheng H et al (2016) Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/beta-catenin signaling. Oncotarget 7, 31413-31428 https://doi.org/10.18632/oncotarget.8920
  5. Ontikatze T, Rudner J, Handrick R, Belka C and Jendrossek V (2014) Dihydroartemisinin is a hypoxia-active anti-cancer drug in colorectal carcinoma cells. Front Oncol 4, 116 https://doi.org/10.3389/fonc.2014.00116
  6. Li Y, Wang Y, Kong R et al (2016) Dihydroartemisinin suppresses pancreatic cancer cells via a microRNA-mRNA regulatory network. Oncotarget 7, 62460-62473 https://doi.org/10.18632/oncotarget.11517
  7. Liao K, Li J and Wang Z (2014) Dihydroartemisinin inhibits cell proliferation via AKT/GSK3beta/cyclinD1 pathway and induces apoptosis in A549 lung cancer cells. Int J Clin Exp Pathol 7, 8684-8691
  8. Zhang S, Shi L, Ma H et al (2017) Dihydroartemisinin induces apoptosis in human gastric cancer cell line BGC-823 through activation of JNK1/2 and p38 MAPK signaling pathways. J Recept Signal Transduct Res 37, 174-180 https://doi.org/10.1080/10799893.2016.1203942
  9. Thongchot S, Vidoni C, Ferraresi A et al (2018) Dihydroartemisinin induces apoptosis and autophagy-dependent cell death in cholangiocarcinoma through a DAPK1-BECLIN1 pathway. Mol Carcinog 57, 1735-1750 https://doi.org/10.1002/mc.22893
  10. Shi X, Wang L, Li X et al (2017) Dihydroartemisinin induces autophagy-dependent death in human tongue squamous cell carcinoma cells through DNA double-strand breakmediated oxidative stress. Oncotarget 8, 45981-45993 https://doi.org/10.18632/oncotarget.17520
  11. Amaravadi R, Kimmelman AC and White E (2016) Recent insights into the function of autophagy in cancer. Genes Dev 30, 1913-1930 https://doi.org/10.1101/gad.287524.116
  12. Acosta JC and Gil J (2012) Senescence: a new weapon for cancer therapy. Trends Cell Biol 22, 211-219 https://doi.org/10.1016/j.tcb.2011.11.006
  13. Itahana K, Campisi J and Dimri GP (2004) Mechanisms of cellular senescence in human and mouse cells. Biogerontology 5, 1-10 https://doi.org/10.1023/B:BGEN.0000017682.96395.10
  14. Chang BD, Xuan Y, Broude EV et al (1999) Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs. Oncogene 18, 4808-4818 https://doi.org/10.1038/sj.onc.1203078
  15. Zhang Z, Yao Z, Zhao S et al (2017) Interaction between autophagy and senescence is required for dihydroartemisinin to alleviate liver fibrosis. Cell Death Dis 8, e2886 https://doi.org/10.1038/cddis.2017.255
  16. Wang SY, Yu QJ, Zhang RD and Liu B (2011) Core signaling pathways of survival/death in autophagy-related cancer networks. Int J Biochem Cell Biol 43, 1263-1266 https://doi.org/10.1016/j.biocel.2011.05.010
  17. Gao X, Luo Z, Xiang T, Wang K, Li J and Wang P (2011) Dihydroartemisinin induces endoplasmic reticulum stressmediated apoptosis in HepG2 human hepatoma cells. Tumori 97, 771-780 https://doi.org/10.1177/030089161109700615
  18. Im E, Yeo C, Lee HJ and Lee EO (2018) Dihydroartemisinin induced caspase-dependent apoptosis through inhibiting the specificity protein 1 pathway in hepatocellular carcinoma SK-Hep-1 cells. Life Sci 192, 286-292 https://doi.org/10.1016/j.lfs.2017.11.008
  19. Qin G, Zhao C, Zhang L et al (2015) Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells. Apoptosis 20, 1072-1086 https://doi.org/10.1007/s10495-015-1132-2
  20. Zhang CZ, Zhang H, Yun J, Chen GG and Lai PB (2012) Dihydroartemisinin exhibits antitumor activity toward hepatocellular carcinoma in vitro and in vivo. Biochem Pharmacol 83, 1278-1289 https://doi.org/10.1016/j.bcp.2012.02.002
  21. Sun P, Yoshizuka N, New L et al (2007) PRAK is essential for ras-induced senescence and tumor suppression. Cell 128, 295-308 https://doi.org/10.1016/j.cell.2006.11.050
  22. Guo X, Deng Y, Lin Y et al (2007) Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis. EMBO J 26, 4709-4719 https://doi.org/10.1038/sj.emboj.7601893
  23. Liu X, Wu J, Fan M et al (2018) Novel dihydroartemisinin derivative DHA-37 induces autophagic cell death through upregulation of HMGB1 in A549 cells. Cell Death Dis 9, 1048 https://doi.org/10.1038/s41419-018-1006-y
  24. Qu C, Ma J, Liu X et al (2017) Dihydroartemisinin exerts anti-tumor activity by inducing mitochondrion and endoplasmic reticulum apoptosis and autophagic cell death in human glioblastoma cells. Mol Carcinog 11, 310
  25. Chen C, Gu P and Wu J (2017) Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nat Commun 8, 14929 https://doi.org/10.1038/ncomms14929
  26. Kocak H, Ballew BJ, Bisht K et al (2014) Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. Genes Dev 28, 2090-2102 https://doi.org/10.1101/gad.248567.114