Next Article in Journal
Gi Protein Modulation of the Potassium Channel TASK-2 Mediates Vesicle Osmotic Swelling to Facilitate the Fusion of Aquaporin-2 Water Channel Containing Vesicles
Previous Article in Journal
The Role of Mitochondria in Reactive Oxygen Species Generation and Its Implications for Neurodegenerative Diseases
Article Menu
Issue 12 (December) cover image

Export Article

Open AccessArticle
Cells 2018, 7(12), 275; https://doi.org/10.3390/cells7120275

Activation of Polyamine Catabolism by N1,N11-Diethylnorspermine in Hepatic HepaRG Cells Induces Dedifferentiation and Mesenchymal-Like Phenotype

1
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
2
Cancer Research Center Lyon, INSERM U1052 and CNRS 5286, Lyon University, 69000 Lyon, France
3
School of Pharmacy, Biocenter Kuopio, University of Eastern Finland, FI-70211 Kuopio, Finland
*
Author to whom correspondence should be addressed.
Received: 21 November 2018 / Revised: 10 December 2018 / Accepted: 15 December 2018 / Published: 18 December 2018
(This article belongs to the Special Issue Epithelial–Mesenchymal Transition and Hallmarks of Cancer)
Full-Text   |   PDF [3298 KB, uploaded 19 December 2018]   |  

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. View Full-Text
Keywords: polyamines; HepaRG; polyamine catabolism; dedifferentiation; EMT; spermidine; polyamine analogues; NextSeq; hepatocytes polyamines; HepaRG; polyamine catabolism; dedifferentiation; EMT; spermidine; polyamine analogues; NextSeq; hepatocytes
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Ivanova, O.N.; Snezhkina, A.V.; Krasnov, G.S.; Valuev-Elliston, V.T.; Khomich, O.A.; Khomutov, A.R.; Keinanen, 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, 7, 275.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Cells EISSN 2073-4409 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top