Abstract
Retinoic acid is one of the most well-known agents able to induce differentiation in several types of tumours. Unfortunately, most of the tumours are refractive to the differentiation cues. The aim of this investigation was to analyse the effects of prolonged treatment with retinoic acid on two cell lines of neural origin refractive to differentiation. Cells were also treated with retinoic acid in combination with a poly(ADP-ribosyl) polymerase (PARP) inhibitor because PARP1 is a known chromatin modulator and can influence the process of differentiation. The main methods comprised tumour cell line culturing and treatment; analysis of RNA and protein expression after cell treatment; as well as analysis of urokinase activity, migration, and proliferation. Both cell lines continued to proliferate under the prolonged treatment and showed increase in urokinase plasminogen activator activity. Analysis of gene expression and cell phenotype revealed different mechanisms, which only in neuroblastoma H4 cells could indicate the process of epithelial-mesenchymal transition. The data collected indicate that the activity of the urokinase plasminogen activator, although belonging to an extracellular protease, does not necessary lead to epithelial-mesenchymal reprogramming and increase in cell migration but can have different outcomes depending on the intracellular milieu.
Highlights
Among many hallmarks of cancer, the prevailing group of features is considering the inability of tumour cells to stop proliferating, either through avoiding senescence, differentiation, cell cycle arrest, or programmed cell death [1]
Due to its influence on the chromatin structure and transcription, we investigated whether it could contribute to retinoic acid-induced cellular processes [9]
The results revealed that A1235 cells increased the urokinase plasminogen activator (uPA) activity several times after all-trans retinoic (ATRA) treatment: two weeks
Summary
Among many hallmarks of cancer, the prevailing group of features is considering the inability of tumour cells to stop proliferating, either through avoiding senescence, differentiation, cell cycle arrest, or programmed cell death [1]. Different chemotherapeutics aim to induce tumour cell death, there are possibilities to cure tumours by induction of the differentiation process, which diminishes the cell’s ability to proliferate. While the treatment of some forms of promyelocytic leukaemia by derivates of retinoic acid is a standard therapy causing cell differentiation, other types of tumours and leukaemia are mostly refractive to differentiation [2,3,4]. RA binds to retinoic acid receptors (RAR) and retinoid X receptors (RXR).
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