Antimalarial Dihydroartemisinin triggers autophagy within HeLa cells of human cervical cancer through Bcl-2 phosphorylation at Ser70.
Antimalarials
/ pharmacology
Antineoplastic Agents
/ pharmacology
Apoptosis
Artemisinins
/ pharmacology
Autophagy
/ drug effects
Beclin-1
/ metabolism
Cisplatin
/ pharmacology
DNA Breaks, Double-Stranded
Female
HeLa Cells
Humans
Phosphorylation
Proto-Oncogene Proteins c-bcl-2
/ chemistry
Reactive Oxygen Species
/ metabolism
TOR Serine-Threonine Kinases
/ metabolism
Up-Regulation
Uterine Cervical Neoplasms
bcl-2 Homologous Antagonist-Killer Protein
/ metabolism
Autophagy
Bcl-2
DNA double-strand break
Dihydroartemisinin
ROS
Journal
Phytomedicine : international journal of phytotherapy and phytopharmacology
ISSN: 1618-095X
Titre abrégé: Phytomedicine
Pays: Germany
ID NLM: 9438794
Informations de publication
Date de publication:
Jan 2019
Jan 2019
Historique:
received:
11
06
2018
revised:
25
08
2018
accepted:
25
09
2018
entrez:
3
1
2019
pubmed:
3
1
2019
medline:
17
4
2019
Statut:
ppublish
Résumé
As an effective antimalarial medicine, Dihydroartemisinin (DHA) has therapeutic potential on human cervical cancer. However, its working mechanism has not been elucidated. This study aimed to investigate the reversal effect of DHA on human cervical cancer HeLa cells, and explored its mechanism of action in vitro and in vivo. The effect and mechanism of DHA on HeLa cells was examined by using CCK-8 assay, flow cytometry, transmission electron microscopy, immunofluorescence, and Western blot analysis in human hepatocellular carcinoma cells. In this study, it was confirmed that DHA had statistically equivalent anti-tumor efficiency in HeLa cells with a clinical chemotherapeutic agent of cisplatin. Meanwhile, DHA triggered autophagy, where LC3B-II expression was dose-dependently increased. Further, it was revealed that DHA promotes reactive oxygen species (ROS) generation, with DNA double-strand breaks (DSB) damage, as up-regulation of γH2AX protein and foci formation. Interestingly, we firstly demonstrated that DHA induced autophagy through promotion of the phosphorylation of Bcl-2 (Ser70), independent of the phosphorylated JNK1/2 (Thr183/Tyr185). Moreover, DHA-treated HeLa cells displayed an increase in the pro-autophagic protein Beclin-1 with downregulated the phospho-mTOR (Ser2448). Furthermore, upregulated pro-apoptotic protein Bak-1, but not Bax, suggesting Bak-1 is included in DHA-induced autophagy. Therefore, DHA upregulates the phosphorylation of Bcl-2 (Ser70) and mTOR (Ser2448) and induces autophagic cell death in Hela cells. This study provided a mechanism to support DHA, an autophagy inducer, as a potential therapeutic agent for human cervical cancer.
Sections du résumé
BACKGROUND
BACKGROUND
As an effective antimalarial medicine, Dihydroartemisinin (DHA) has therapeutic potential on human cervical cancer. However, its working mechanism has not been elucidated.
PURPOSE
OBJECTIVE
This study aimed to investigate the reversal effect of DHA on human cervical cancer HeLa cells, and explored its mechanism of action in vitro and in vivo.
STUDY DESIGN/METHODS
METHODS
The effect and mechanism of DHA on HeLa cells was examined by using CCK-8 assay, flow cytometry, transmission electron microscopy, immunofluorescence, and Western blot analysis in human hepatocellular carcinoma cells.
RESULTS
RESULTS
In this study, it was confirmed that DHA had statistically equivalent anti-tumor efficiency in HeLa cells with a clinical chemotherapeutic agent of cisplatin. Meanwhile, DHA triggered autophagy, where LC3B-II expression was dose-dependently increased. Further, it was revealed that DHA promotes reactive oxygen species (ROS) generation, with DNA double-strand breaks (DSB) damage, as up-regulation of γH2AX protein and foci formation. Interestingly, we firstly demonstrated that DHA induced autophagy through promotion of the phosphorylation of Bcl-2 (Ser70), independent of the phosphorylated JNK1/2 (Thr183/Tyr185). Moreover, DHA-treated HeLa cells displayed an increase in the pro-autophagic protein Beclin-1 with downregulated the phospho-mTOR (Ser2448). Furthermore, upregulated pro-apoptotic protein Bak-1, but not Bax, suggesting Bak-1 is included in DHA-induced autophagy.
CONCLUSION
CONCLUSIONS
Therefore, DHA upregulates the phosphorylation of Bcl-2 (Ser70) and mTOR (Ser2448) and induces autophagic cell death in Hela cells. This study provided a mechanism to support DHA, an autophagy inducer, as a potential therapeutic agent for human cervical cancer.
Identifiants
pubmed: 30599894
pii: S0944-7113(18)30503-8
doi: 10.1016/j.phymed.2018.09.221
pii:
doi:
Substances chimiques
Antimalarials
0
Antineoplastic Agents
0
Artemisinins
0
BAK1 protein, human
0
BCL2 protein, human
0
Beclin-1
0
Proto-Oncogene Proteins c-bcl-2
0
Reactive Oxygen Species
0
bcl-2 Homologous Antagonist-Killer Protein
0
artenimol
6A9O50735X
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
147-156Informations de copyright
Copyright © 2018. Published by Elsevier GmbH.