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DJ-1 mediates the resistance of cancer cells to dihydroartemisinin through reactive oxygen species removal
Zhu H.2; Liao S.-D.2; Shi J.-J.4; Chang L.-L.2; Tong Y.-G.1; Cao J.2; Fu Y.-Y.2; Chen X.-P.3; Ying M.-D.2; Yang B.2; He Q.-J.2; Lu J.-J.3
2014
Source PublicationFree Radical Biology and Medicine
ISSN18734596 08915849
Volume71Pages:121-132
Abstract

Dihydroartemisinin (DHA), one of the main metabolites of artemisinin and its derivatives, presents anti-cancer potential in vitro and in vivo. To explore the mechanisms of resistance toward DHA, a DHA-resistant cell line, HeLa/DHA, was established with a resistance factor of 7.26 in vitro. Upon DHA treatment, apoptotic cells were significantly elicited in parental HeLa cells but minimally induced in HeLa/DHA cells. HeLa/DHA cells also displayed much less sensitivity to DHA-induced tumor suppression in cancer xenograft models than HeLa cells. Intriguingly, DHA-resistant cells did not display a multidrug-resistant phenotype. Based on a proteomic study employing LC-ESI-MS/MS together with pathway analysis, DJ-1 (PARK7) was found to be highly expressed in HeLa/DHA cells. Western blot and immunofluorescence assays confirmed the higher expression of DJ-1 in HeLa/DHA cells than in parental cells in both cell line and xenograft models. DJ-1 is translocated to the mitochondria of HeLa/DHA cells and oxidized, providing DJ-1 with stronger cytoprotection activity. Further study revealed that DJ-1 knockdown in HeLa/DHA cells abolished the observed resistance, whereas overexpression of DJ-1 endowed the parental HeLa cells with resistance toward DHA. Reactive oxygen species (ROS) were also significantly induced by either DHA or hydrogen peroxide in HeLa cells but not in resistant HeLa/DHA cells. When the cells were pretreated with N-acetyl-l-cysteine, the effect of DJ-1 knockdown on sensitizing HeLa/DHA cells to DHA was significantly attenuated. In summary, our study suggests that overexpression and mitochondrial translocation of DJ-1 provides HeLa/DHA cells with resistance to DHA-induced ROS and apoptosis. © 2014 Elsevier Inc. All rights reserved.

KeywordDihydroartemisinin Dj-1 Free Radicals Mitochondria Proteomic Resistant
DOI10.1016/j.freeradbiomed.2014.03.026
URLView the original
Indexed BySCI
WOS Research AreaBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS SubjectBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS IDWOS:000336891100011
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Cited Times [WOS]:16   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.University of California, Los Angeles
2.Zhejiang University
3.Universidade de Macau
4.Zhejiang Chinese Medical University
Recommended Citation
GB/T 7714
Zhu H.,Liao S.-D.,Shi J.-J.,et al. DJ-1 mediates the resistance of cancer cells to dihydroartemisinin through reactive oxygen species removal[J]. Free Radical Biology and Medicine,2014,71:121-132.
APA Zhu H..,Liao S.-D..,Shi J.-J..,Chang L.-L..,Tong Y.-G..,...&Lu J.-J..(2014).DJ-1 mediates the resistance of cancer cells to dihydroartemisinin through reactive oxygen species removal.Free Radical Biology and Medicine,71,121-132.
MLA Zhu H.,et al."DJ-1 mediates the resistance of cancer cells to dihydroartemisinin through reactive oxygen species removal".Free Radical Biology and Medicine 71(2014):121-132.
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