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Inhibition of cell proliferation and migration through nucleobase-modified polyamidoamine-mediated p53 delivery.

ABSTRACT: The nucleobase 2-amino-6-chloropurine-modified polyamidoamine (AP-PAMAM) was used as a carrier for p53 gene delivery to achieve the antitumor effects.The condensation of p53 plasmid was studied through gel retardation assay, and the transfection efficiency was evaluated through the transfection assay of pEGFP-N3 and pGL-3 plasmids. Using human cervical carcinoma cell line HeLa as a model, the inhibition of cell proliferation and migration was studied through flow cytometry, wound healing and Transwell migration assays, respectively. The p53 expression level was detected through quantitative polymerase chain reaction and Western blotting analyses.The carrier could condense p53 plasmid into stable nanoparticles at N/P ratios of 2.0, and higher transfection efficiency than polyamidoamine (PAMAM) could be obtained at all the N/P ratios studied. AP-PAMAM-mediated p53 delivery could achieve stronger antiproliferative effect than PAMAM/p53. The antiproliferative effect was identified to be triggered by the induction of cell apoptosis (apoptotic ratio of 26.17%) and cell cycle arrest at S phase. Additionally, AP-PAMAM/p53 transfection has been found to suppress the cell migration and invasion of cancer cells. Finally, the enhanced p53 expression level could be detected after p53 transfection at mRNA and protein levels.The PAMAM derivative-mediated p53 delivery could be a promising strategy for achieving tumor gene therapy.

SUBMITTER: Han H

PROVIDER: S-EPMC5846749 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Inhibition of cell proliferation and migration through nucleobase-modified polyamidoamine-mediated p53 delivery.

Han Haobo H Chen Wenqi W Yang Jiebing J Liang Xiao X Wang Yudi Y Li Quanshun Q Yang Yan Y Li Kun K

International journal of nanomedicine 20180306

<h4>Introduction</h4>The nucleobase 2-amino-6-chloropurine-modified polyamidoamine (AP-PAMAM) was used as a carrier for <i>p53</i> gene delivery to achieve the antitumor effects.<h4>Methods and materials</h4>The condensation of <i>p53</i> plasmid was studied through gel retardation assay, and the transfection efficiency was evaluated through the transfection assay of pEGFP-N3 and pGL-3 plasmids. Using human cervical carcinoma cell line HeLa as a model, the inhibition of cell proliferation and mi ...[more]

PMID: 29563788

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Project description:Epithelial-mesenchymal transition (EMT) is a cellular process in which epithelial cells are partially transformed into stromal cells, which endows the polarized epithelium cells more invasive feature and contributes cancer metastasis and drug resistance. Ferritinophagy is an event of ferritin degradation in lysosomes, which contributes Fenton-mediated ROS production. In addition, some studies have shown that ROS participates in EMT process, but the effect of ROS stemmed from ferritin degradation on EMT has not been fully established. A novel iron chelator, DpdtC (2,2'-di-pyridylketone dithiocarbamate), which could induce ferritinophagy in HepG2 cell in our previous study, was used to investigate its effect on EMT in gastric cancer cells. The proliferation assay showed that DpdtC treatment resulted in growth inhibition and morphologic alteration in MGC-803 cell (IC50 = 3.1 ± 0.3??M), and its action involved ROS production that was due to the occurrence of ferritinophagy. More interestingly, DpdtC could also inhibit EMT, leading to the upregulation of E-cadherin and the downregulation of vimentin; however, the addition of NAC and 3-MA could attenuate (or neutralize) the action of DpdtC on ferritinophagy induction and EMT inhibition, supporting that the enhanced ferritinophagic flux contributed to the EMT inhibition. Since the degradation of ferritin may trigger the production of ROS and induce the response of p53, we next studied the role of p53 in the above two-cell events. As expected, an upregulation of p53 was observed after DpdtC insulting; however, the addition of a p53 inhibitor, PFT-?, could significantly attenuate the action of DpdtC on ferritinophagy induction and EMT inhibition. In addition, autophagy inhibitors or NAC could counteract the effect of DpdtC and restore the level of p53 to the control group, indicating that the upregulation of p53 was caused by ferritinophagy-mediated ROS production. In conclusion, our data demonstrated that the inhibition of EMT induced by DpdtC was realized through ferritinophagy-mediated ROS/p53 pathway, which supported that the activation of ferritinophagic flux was the main driving force in EMT inhibition in gastric cancer cells, and further strengthening the concept that NCOA4 participates in EMT process.

Dataset Information

Inhibition of cell proliferation and migration through nucleobase-modified polyamidoamine-mediated p53 delivery.

Publications

Inhibition of cell proliferation and migration through nucleobase-modified polyamidoamine-mediated p53 delivery.

Similar Datasets

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