Mechanism of dihydroartemisinin-induced apoptosis in prostate cancer PC3 cells: An iTRAQ-based proteomic analysis

Xu, Guohai; Wenqin, Zou; Du, Shijuan; Wu, Mei‐Hwan; Xiang, Tingxiu; Luo, Zhijun

doi:10.1016/j.lfs.2016.05.033

Cited by 25 publications

(15 citation statements)

References 95 publications

(107 reference statements)

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“…The morphology of A549 cells was observed by TEM as described previously. 62 Briefly, cells were centrifuged at 1000 × g for 5 min after trypsinization, fixed with 4% glutaraldehyde in 0.1M PBS (pH 7.4) for 2 h at 4 °C, washed three times with PBS (pH 7.4) and post-fixed with 1% osmium tetroxide in 0.1 M PBS for 1 h at 4 °C, dehydrated in a graded series of alcohol and acetone, and then embedded in Epon 816. The ultrathin sections were obtained using a Leica ultramicrotome (Leica Microsystems, Buffalo Grove, IL, USA).…”

Section: Methodsmentioning

confidence: 99%

Zinc oxide nanoparticles harness autophagy to induce cell death in lung epithelial cells

et al. 2017

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Although zinc oxide nanoparticles (ZnONPs) are widely used, they have raised concerns of toxicity in humans. Previous studies have indicated that reactive oxygen species (ROS) and autophagy are involved in the cytotoxicity of ZnONPs, but the regulatory mechanisms between autophagy and ROS remain to be elucidated. Herein, we comprehensively investigated the regulatory mechanism of autophagy and the link between autophagy and ROS in ZnONPs-treated lung epithelial cells. We demonstrated that ZnONPs could induce autophagy, and this process could enhance the dissolution of ZnONPs in lysosomes to release zinc ions. Sequentially, zinc ions released from ZnONPs were able to damage not only lysosomes, leading to impaired autophagic flux, but also mitochondria. Impaired autophagic flux resulted in the accumulation of damaged mitochondria, which could generate excessive ROS to cause cell death. We further demonstrated that the inhibition of autophagy by either pharmacological inhibitors or small interfering RNA (siRNA)-mediated knockdown of Beclin-1 and AMP-activated protein kinase could ameliorate ZnONPs-induced cell death. Moreover, we found that lysosomal-associated membrane protein 1/2 (LAMP-1/2), which were the most abundant highly glycosylated protein in late endosomes/lysosomes, exhibited aberrant expression pattern upon treatment with ZnONPs. Intriguingly, LAMP-2 knockdown, but not LAMP-1 knockdown, could exacerbate the ROS generation and cell death induced by ZnONPs treatment. Meanwhile, LAMP-2 overexpression alleviated ZnONPs-induced cell death, suggesting that LAMP-2 was linked to this toxic phenotype induced by ZnONPs. Our results indicate that autophagic dysfunction could contribute to excessive ROS generation upon treatment with ZnONPs in lung epithelial cells, suggesting that modulating the autophagy process would minimize ZnONPs-associated toxicity.

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Section: Methodsmentioning

confidence: 99%

Zinc oxide nanoparticles harness autophagy to induce cell death in lung epithelial cells

et al. 2017

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“…Recent studies strongly supported that the activation of autophagic cell death was a possible tumor suppression mechanism, which suggested cell death could occur associated with features of autophagy (Kroemer and Levine, 2008 ; Salazar et al, 2009 ; Liu and Levine, 2015 ). Previous studies have found that DHA induced apoptosis in human gastric cancer and prostate cancer cells (Xu G. et al, 2016 ; Zhang et al, 2017 ) and activated the autophagy program in several cancer cells (Hu et al, 2014 ). However, whether DHA induces apoptosis and autophagy in human GBM cells needs to be explored urgently.…”

Section: Introductionmentioning

confidence: 97%

Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells

Liu

et al. 2017

Front. Cell. Neurosci.

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Glioblastoma (GBM) is the most advanced and aggressive form of gliomas. Dihydroartemisinin (DHA) has been shown to exhibit anti-tumor activity in various cancer cells. However, the effect and molecular mechanisms underlying its anti-tumor activity in human GBM cells remain to be elucidated. Our results proved that DHA treatment significantly reduced cell viability in a dose- and time-dependent manner by CCK-8 assay. Further investigation identified that the cell viability was rescued by pretreatment either with Z-VAD-FMK, 3-methyladenine (3-MA) or in combination. Moreover, DHA induced apoptosis of GBM cells through mitochondrial membrane depolarization, release of cytochrome c and activation of caspases-9. Enhanced expression of GRP78, CHOP and eIF2α and activation of caspase 12 were additionally confirmed that endoplasmic reticulum (ER) stress pathway of apoptosis was involved in the cytotoxicity of DHA. DHA-treated GBM cells exhibited the morphological and biochemical changes typical of autophagy. Co-treatment with chloroquine (CQ) significantly induced the above effects. Furthermore, ER stress and mitochondrial dysfunction were involved in the DHA-induced autophagy. Further study revealed that accumulation of reactive oxygen species (ROS) was attributed to the DHA induction of apoptosis and autophagy. The illustration of these molecular mechanisms will present a novel insight for the treatment of human GBM.

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“…Dihydroartemisinin (DHA), a semisynthetic derivative of ART and a novel anti-malarial agent, has fewer side effects than ART5. The biological activity of DHA in addition to its anti-malarial role suggests that it inhibits growth of cancer cells, suppresses estrogen deficiency-induced osteoporosis and osteoblast remodeling, and inhibits tumor angiogenesis67. The inhibitory role of DHA on inflammation- and catabolism-associated genes has also been reported89.…”

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confidence: 99%

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

Jiang

Meng

Lee

et al. 2016

Sci Rep

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Osteoarthritis is a disease with inflammatory and catabolic imbalance in cartilage. Dihydroartemisinin (DHA), a natural and safe anti-malarial agent, has been reported to inhibit inflammation, but its effects on chondrocytes have yet to be elucidated. We investigated the effects of DHA on catabolism in chondrocytes. Viability of SD rats chondrocytes was analyzed. Autophagy levels were determined via expression of autophagic markers LC3 and ATG5, GFP-LC3 analysis, acridine orange staining, and electron microscopy. ATG5 siRNA induced autophagic inhibition. Catabolic gene and chemokine expression was evaluated using qPCR. The NF-κB inhibitor SM7368 and p65 over-expression were used to analyze the role of NF-κB pathway in autophagic activation. A concentration of 1 μM DHA without cytotoxicity increased LC3-II and ATG5 levels as well as autophagosomal numbers in chondrocytes. DHA inhibited TNF-α-induced expression of MMP-3 and -9, ADAMTS5, CCL-2 and -5, and CXCL1, which was reversed by autophagic inhibition. TNF-α-stimulated nuclear translocation and degradation of the p65 and IκBα proteins, respectively, were attenuated in DHA-treated chondrocytes. NF-κB inhibition activated autophagy in TNF-α-treated chondrocytes, but p65 over-expression reduced the autophagic response to DHA. These results indicate that DHA might suppress the levels of catabolic and inflammatory factors in chondrocytes by promoting autophagy via NF-κB pathway inhibition.

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Mechanism of dihydroartemisinin-induced apoptosis in prostate cancer PC3 cells: An iTRAQ-based proteomic analysis

Cited by 25 publications

References 95 publications

Zinc oxide nanoparticles harness autophagy to induce cell death in lung epithelial cells

Zinc oxide nanoparticles harness autophagy to induce cell death in lung epithelial cells

Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

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