Open Access
Cells, volume 7, issue 12, pages 275
Activation of Polyamine Catabolism by N1,N11-Diethylnorspermine in Hepatic HepaRG Cells Induces Dedifferentiation and Mesenchymal-Like Phenotype
Ivanova Olga N
1
,
Snezhkina Anastasiya V.
1
,
Krasnov George S.
1
,
Valuev-Elliston Vladimir T.
1
,
Khomich Olga A
1, 2
,
Khomutov Alexey R
1
,
Keinänen Tuomo A.
3
,
Alhonen Leena
3
,
Bartosch Birke
2
,
Kudryavtseva Anna V.
1
,
2
Cancer Research Center Lyon, INSERM U1052 and CNRS 5286, Lyon University, 69000 Lyon, France
|
Publication type: Journal Article
Publication date: 2018-12-18
PubMed ID:
30567412
General Medicine
Abstract
Tumorigenesis is accompanied by the metabolic adaptation of cells to support enhanced proliferation rates and to optimize tumor persistence and amplification within the local microenvironment. In particular, cancer cells exhibit elevated levels of biogenic polyamines. Inhibitors of polyamine biosynthesis and inducers of their catabolism have been evaluated as antitumor drugs, however, their efficacy and safety remain controversial. Our goal was to investigate if drug-induced modulation of polyamine metabolism plays a role in dedifferentiation using differentiated human hepatocyte-like HepaRG cell cultures. N1,N11-diethylnorspermine (DENSpm), a potent inducer of polyamine catabolism, triggered an epithelial-mesenchymal transition (EMT)-like dedifferentiation in HepaRG cultures, as shown by down-regulation of mature hepatocytes markers and upregulation of classical EMT markers. Albeit the fact that polyamine catabolism produces H2O2, DENSpm-induced de-differentiation was not affected by antioxidants. Use of a metabolically stable spermidine analogue showed furthermore, that spermidine is a key regulator of hepatocyte differentiation. Comparative transcriptome analyses revealed, that the DENSpm-triggered dedifferentiation of HepaRG cells was accompanied by dramatic metabolic adaptations, exemplified by down-regulation of the genes of various metabolic pathways and up-regulation of the genes involved in signal transduction pathways. These results demonstrate that polyamine metabolism is tightly linked to EMT and differentiation of liver epithelial cells.
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Ivanova O. N. et al. Activation of Polyamine Catabolism by N1,N11-Diethylnorspermine in Hepatic HepaRG Cells Induces Dedifferentiation and Mesenchymal-Like Phenotype // Cells. 2018. Vol. 7. No. 12. p. 275.
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Ivanova O. N., Snezhkina A. V., Krasnov G. S., Valuev-Elliston V. T., Khomich O. A., Khomutov A. R., Keinänen T. A., Alhonen L., Bartosch B., Kudryavtseva A. V., Kochetkov S. N., IVANOV A. V. Activation of Polyamine Catabolism by N1,N11-Diethylnorspermine in Hepatic HepaRG Cells Induces Dedifferentiation and Mesenchymal-Like Phenotype // Cells. 2018. Vol. 7. No. 12. p. 275.
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TY - JOUR
DO - 10.3390/cells7120275
UR - https://doi.org/10.3390%2Fcells7120275
TI - Activation of Polyamine Catabolism by N1,N11-Diethylnorspermine in Hepatic HepaRG Cells Induces Dedifferentiation and Mesenchymal-Like Phenotype
T2 - Cells
AU - Ivanova, Olga N
AU - Snezhkina, Anastasiya V.
AU - Krasnov, George S.
AU - Valuev-Elliston, Vladimir T.
AU - Khomich, Olga A
AU - Khomutov, Alexey R
AU - Alhonen, Leena
AU - Kochetkov, Sergey N.
AU - IVANOV, Alexander V.
AU - Keinänen, Tuomo A.
AU - Bartosch, Birke
AU - Kudryavtseva, Anna V.
PY - 2018
DA - 2018/12/18 00:00:00
PB - Multidisciplinary Digital Publishing Institute (MDPI)
SP - 275
IS - 12
VL - 7
PMID - 30567412
SN - 2073-4409
ER -
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@article{2018_Ivanova,
author = {Olga N Ivanova and Anastasiya V. Snezhkina and George S. Krasnov and Vladimir T. Valuev-Elliston and Olga A Khomich and Alexey R Khomutov and Leena Alhonen and Sergey N. Kochetkov and Alexander V. IVANOV and Tuomo A. Keinänen and Birke Bartosch and Anna V. Kudryavtseva},
title = {Activation of Polyamine Catabolism by N1,N11-Diethylnorspermine in Hepatic HepaRG Cells Induces Dedifferentiation and Mesenchymal-Like Phenotype},
journal = {Cells},
year = {2018},
volume = {7},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
month = {dec},
url = {https://doi.org/10.3390%2Fcells7120275},
number = {12},
pages = {275},
doi = {10.3390/cells7120275}
}
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Ivanova, Olga N., et al. “Activation of Polyamine Catabolism by N1,N11-Diethylnorspermine in Hepatic HepaRG Cells Induces Dedifferentiation and Mesenchymal-Like Phenotype.” Cells, vol. 7, no. 12, Dec. 2018, p. 275. https://doi.org/10.3390%2Fcells7120275.