期刊
CELLS
卷 7, 期 12, 页码 -出版社
MDPI
DOI: 10.3390/cells7120275
关键词
polyamines; HepaRG; polyamine catabolism; dedifferentiation; EMT; spermidine; polyamine analogues; NextSeq; hepatocytes
类别
资金
- Russian Science Foundation [14-14-01021]
- French National Agency for AIDS and Viral Hepatitis Research [14370]
- Comite de Saone-et-Loire de la Ligue contre le cancer
- Agence Nationale de Recherche
- Region Rhone-Alpes
- DevWeCan French Laboratories of Excellence Network (Labex) [ANR-10-LABX-61]
- OpeRa IHU program [ANR-10-IBHU-004]
- University of Eastern Finland
- Russian Science Foundation [14-14-01021] Funding Source: Russian Science Foundation
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. N-1,N-11-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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