Ezrin dephosphorylation/downregulation contributes to ursolic acid-mediated cell death in human leukemia cells

Li, G; Zhou, Tao; Liu, L; Chen, J; Zhao, Zhiyao; Peng, Yongbo; Li, P; Gao, Ning

doi:10.1038/bcj.2013.7

Cited by 25 publications

(16 citation statements)

References 41 publications

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“…After 4 weeks of treatment, mice were killed by cervical dislocation, and tumour tissues were harvested and fixed in 4% paraformaldehyde or frozen at −80°C. Histological, immunohistochemical and immunofluorescence analyses were performed as described . TdT‐mediated dUTP nick‐end labelling (TUNEL) analysis was used to detect the dead cells in the tissue samples with In Stitu Cell Death Detection kit (Roche, Mannheim, Germany) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Tang

Liu

Zhang

et al. 2018

J Cellular Molecular Medi

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IR‐783 is a kind of heptamethine cyanine dye that exhibits imaging, cancer targeting and anticancer properties. A previous study reported that its imaging and targeting properties were related to mitochondria. However, the molecular mechanism behind the anticancer activity of IR‐783 has not been well demonstrated. In this study, we showed that IR‐783 inhibits cell viability and induces mitochondrial apoptosis in human breast cancer cells. Exposure of MDA‐MB‐231 cells to IR‐783 resulted in the loss of mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) depletion, mitochondrial permeability transition pore (mPTP) opening and cytochrome c (Cyto C) release. Furthermore, we found that IR‐783 induced dynamin‐related protein 1 (Drp1) translocation from the cytosol to the mitochondria, increased the expression of mitochondrial fission proteins mitochondrial fission factor (MFF) and fission‐1 (Fis1), and decreased the expression of mitochondrial fusion proteins mitofusin1 (Mfn1) and optic atrophy 1 (OPA1). Moreover, knockdown of Drp1 markedly blocked IR‐783‐mediated mitochondrial fission, loss of MMP, ATP depletion, mPTP opening and apoptosis. Our in vivo study confirmed that IR‐783 markedly inhibited tumour growth and induced apoptosis in an MDA‐MB‐231 xenograft model in association with the mitochondrial translocation of Drp1. Taken together, these findings suggest that IR‐783 induces apoptosis in human breast cancer cells by increasing Drp1‐mediated mitochondrial fission. Our study uncovered the molecular mechanism of the anti‐breast cancer effects of IR‐783 and provided novel perspectives for the application of IR‐783 in the treatment of breast cancer.

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Section: Methodsmentioning

confidence: 99%

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Tang

Liu

Zhang

et al. 2018

J Cellular Molecular Medi

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“…The tumors were excised and were either formalin-fixed or flash-frozen at − 20°C. H&E, TUNEL, and immunohistochemical analyses were performed as previously described [30].…”

Section: Xenograft Assaymentioning

confidence: 99%

ROCK1 activation-mediated mitochondrial translocation of Drp1 and cofilin are required for arnidiol-induced mitochondrial fission and apoptosis

Zhang

et al. 2020

J Exp Clin Cancer Res

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Background: Arnidiol is a pentacyclic triterpene diol that has multiple pharmacological activities. However, the apoptotic activities of arnidiol in human cancer cells have not yet been explored, nor has the mechanism by which arnidiol induces apoptosis been examined in depth. Methods: MDA-MB-231 cells and xenografted mice were treated with arnidiol. Mitochondrial fission and apoptosis were determined by immunofluorescence, flow cytometry and related molecular biological techniques. The interaction and colocalization of cofilin and Drp1 was determined by immunoprecipitation and immunofluorescence assays. Results: Arnidiol induces mitochondrial fission and apoptosis through mitochondrial translocation of Drp1 and cofilin. Importantly, the interaction of Drp1 and cofilin in mitochondria is involved in arnidiol-induced mitochondrial fission and apoptosis. Knockdown of either Drp1 or cofilin abrogated arnidiol-induced mitochondrial translocation, interaction of Drp1 and cofilin, mitochondrial fission and apoptosis. Only dephosphorylated Drp1 (Ser637) and cofilin (Ser3) were translocated to the mitochondria. Mutants of Drp1 S637A and cofilin S3A, which mimic the dephosphorylated forms, enhanced mitochondrial fission and apoptosis induced by arnidiol, whereas mutants of Drp1 S637D and cofilin S3E, which mimic the phosphorylated forms, suppressed mitochondrial fission and apoptosis induced by arnidiol. A mechanistic study revealed that ROCK1 activation plays an important role in the arnidiol-mediated Drp1 and cofilin dephosphorylation and mitochondrial translocation, mitochondrial fission, and apoptosis. Conclusions: Our data reveal a novel role of both Drp1 and cofilin in the regulation of mitochondrial fission and apoptosis and suggest that arnidiol could be developed as a potential agent for the treatment of human cancer.

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“…Many studies showed the multi-biological functions of ursolic acid, including anti-oxidant and anti-inflammatory activity 16. Also, ursolic acid has anti-cancer activity by inhibiting proliferation and stimulating apoptosis in prostate cancer 17, 18, colon cancer 19, 20, breast cancer 21, ovarian cancer 22, leukemia 23 and melanoma 24.…”

Section: Introductionmentioning

confidence: 99%

Blockage of epithelial to mesenchymal transition and upregulation of let 7b are critically involved in ursolic acid induced apoptosis in malignant mesothelioma cell

Sohn¹,

Won²,

Lee³

et al. 2016

Int. J. Biol. Sci.

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Malignant pleural mesothelioma (MPN), which is caused by asbestos exposure, is one of aggressive lung tumors. In the present study, we elucidated the anti-tumor mechanism of ursolic acid in malignant mesotheliomas. Ursolic acid significantly exerted cytotoxicity in a time and dose dependent manner in H28, H2452 and MSTO-211H mesothelioma cells and inhibited cell proliferation by colony formation assay in a dose-dependent fashion. Also, ursolic acid treatment accumulated the sub-G1 population, attenuated the expression of procapase 9, cyclin D1, pAKT, p-glycogen synthase kinase 3-alpha/beta (pGSK3α/β), β-catenin and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and also cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP) in mesothelioma cells. Furthermore, ursolic acid treatment blocked epithelial and mesenchymal transition (EMT) molecules by activating E-cadherin as an epithelial marker and attenuating Vimentin, and Twist as mesenchymal molecules. Interestingly, miRNA array revealed that 23 miRNAs (>2 folds) including let-7b and miRNA3613-5p, miRNA134 and miRNA196b were significantly upregulated while 33 miRNAs were downregulated in ursolic acid treated H2452 cells. Furthermore, overexpression of let 7b using let-7b mimics enhanced the antitumor effect of ursolic acid to attenuate the expression of procaspases 3, pro-PARP, pAKT, β-catenin and Twist and increase sub-G1 accumulation in H2452 mesothelioma cells. Overall, our findings suggest that ursolic acid induces apoptosis via inhibition of EMT and activation of let7b in mesothelioma cells as a potent chemotherapeutic agent for treatment of malignant mesotheliomas.

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Ezrin dephosphorylation/downregulation contributes to ursolic acid-mediated cell death in human leukemia cells

Cited by 25 publications

References 41 publications

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

ROCK1 activation-mediated mitochondrial translocation of Drp1 and cofilin are required for arnidiol-induced mitochondrial fission and apoptosis

Blockage of epithelial to mesenchymal transition and upregulation of let 7b are critically involved in ursolic acid induced apoptosis in malignant mesothelioma cell

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