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

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.

HIV-1 Reverse Transcriptase Promotes Tumor Growth and Metastasis Formation via ROS-Dependent Upregulation of Twist

“…Cells treated with oxidants tert -butylhydroquinone (tBHQ) (Sigma, Darmstadt, Germany) and H 2 O 2 at 100 μ M concentrations were used as positive controls of ROS induction. Antioxidants N-acetyl cysteine (NAC) in concentration 5 mM were used as a general inhibitor of ROS production, [44], and tocopherol (both from Sigma, Darmstadt, Germany) in concentration 1 μ M, as the inhibitor of lipid peroxidation [45].…”

ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells

“…The association of increased SMOX expression and chronic inflammation was also observed in several precancerous conditions such as prostatic intraepithelial neoplasia (PIN) and chronic hepatitis [105–107]. Interestingly, drug-induced modulation of polyamine catabolism in hepatic cells results in them undergoing an epithelial-mesenchymal transition- (EMT-) like dedifferentiation, which is not, however, associated with elevated ROS levels [108]. This can indicate that ROS overproduction caused by increased polyamine catabolism together with chronic inflammation could be a precursor event of cancer development, but not tumor progression (with respect to metastasis).…”

Cultivation of Cells in a Physiological Plasmax Medium Increases Mitochondrial Respiratory Capacity and Reduces Replication Levels of RNA Viruses

“…Numerous lines of evidence show that cell proliferation, (de)differentiation, or activation is associated with remodeling of metabolism: the shift between glycolysis and mitochondrial respiration as well as with changes in other catabolic/anabolic pathways and redox systems [ 4 , 5 , 6 , 7 , 8 ]. In recent years, it has become clear that the investigation of cellular metabolism is affected by cell cultivation conditions.…”