p53 Mediates Colistin-Induced Autophagy and Apoptosis in PC-12 Cells
| Autor: | Jichang Li, Wei Xu, Rui Wang, Ziyin Lu, Li Li, Maria Lourdes Regina Hughes, Jinli Wang, Guozheng Jiang, Jian Li, Yuan Sun, Xueping Chen, Chunli Xia, Daoyuan Xie, Rui Li, Ling Zhang, Feng Qian |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Programmed cell death Cellular differentiation Apoptosis AMP-Activated Protein Kinases PC12 Cells 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Bcl-2-associated X protein Autophagy Animals Pharmacology (medical) p53 upregulated modulator of apoptosis Benzothiazoles bcl-2-Associated X Protein Neurons Pharmacology biology Caspase 3 Colistin TOR Serine-Threonine Kinases Membrane Proteins Cell Differentiation biochemical phenomena metabolism and nutrition Pifithrin Molecular biology Anti-Bacterial Agents Rats Cell biology 030104 developmental biology Infectious Diseases Gene Expression Regulation chemistry 030220 oncology & carcinogenesis biology.protein Tumor Suppressor Protein p53 Signal transduction Apoptosis Regulatory Proteins Microtubule-Associated Proteins Signal Transduction Toluene |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 60:5294-5301 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | The mechanism of colistin-induced neurotoxicity is still unknown. Our recent study (L. Zhang, Y. H. Zhao, W. J. Ding, G. Z. Jiang, Z. Y. Lu, L. Li, J. L. Wang, J. Li, and J. C. Li, Antimicrob Agents Chemother 59:2189–2197, 2015, http://dx.doi.org/10.1128/AAC.04092-14 ; H. Jiang, J. C. Li, T. Zhou, C. H. Wang, H. Zhang, and H. Wang, Int J Mol Med 33:1298–1304, 2014, http://dx.doi.org/10.3892/ijmm.2014.1684 ) indicates that colistin induces autophagy and apoptosis in rat adrenal medulla PC-12 cells, and there is interplay between both cellular events. As an important cellular stress sensor, phosphoprotein p53 can trigger cell cycle arrest and apoptosis and regulate autophagy. The aim of the present study was to investigate the involvement of the p53 pathway in colistin-induced neurotoxicity in PC-12 cells. Specifically, cells were treated with colistin (125 μg/ml) in the absence and presence of a p53 inhibitor, pifithrin-α (PFT-α; 20 nM), for 12 h and 24 h, and the typical hallmarks of autophagy and apoptosis were examined by fluorescence/immunofluorescence microscopy and electron microscopy, real-time PCR, and Western blotting. The results indicate that colistin had a stimulatory effect on the expression levels of the target genes and proteins involved in autophagy and apoptosis, including LC3-II/I, p53, DRAM (damage-regulated autophagy modulator), PUMA (p53 upregulated modulator of apoptosis), Bax, p-AMPK (activated form of AMP-activated protein kinase), and caspase-3. In contrast, colistin appeared to have an inhibitory effect on the expression of p-mTOR (activated form of mammalian target of rapamycin), which is another target protein in autophagy. Importantly, analysis of the levels of p53 in the cells treated with colistin revealed an increase in nuclear p53 at 12 h and cytoplasmic p53 at 24 h. Pretreatment of colistin-treated cells with PFT-α inhibited autophagy and promoted colistin-induced apoptosis. This is the first study to demonstrate that colistin-induced autophagy and apoptosis are associated with the p53-mediated pathway. |
| Databáze: | OpenAIRE |
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