MiR-155-5p-mediated increase in p53 content induced by dacarbazine in melanoma cells

Abstract

BACKGROUND: Cellular senescence is a stress response, triggered by various stimuli such as chemotherapy treatment and causes G₀/G₁ cell cycle arrest followed by the production of a senescence associated secretory phenotype. p53 considered to be a modulator of these events although the precise mechanisms of it remains not clear.

AIMS: To determine the non-apoptotic functions of the p53 protein — the formation of the senescence associated secretory phenotype phenotype of melanoma cells under the treatment of the cytostatic agent dacarbazine.

MATERIALS AND METHODS: The study was conducted on BRO and SK-MEL-2 skin melanoma cell lines. Melanoma cells were were treated by cytostatic agent dacarbazine. Then immunocytochemical study was performed to determine the proportion of G₀-positive cells and the expression of the tumor suppressor protein p53. A bioinformatic analysis was accomplished to identify for p53 regulators with determining of miR-155-5p levels in exosomes released by dacarbazine-treated melanoma cells.

RESULTS: The cytostatic drug dacarbazine increases the proportion of cells residing in the G₀ phase of the cell cycle. Onco-microRNA miR-155-5p was expressed in the exosomes of the two studied cell lines BRO and SK-MEL-2 of skin melanoma. Changes in the expression level of p53 correlate with changes in miR-155-5p microRNA expression. The absence of changes in p53 expression in BRO melanoma cells may be due to the absence of changes in miR-155-5p expression levels. In the BRO cell line, no changes in the expression of the oncosuppressor p53 were observed with an increased percentage of G₀-positive cells, which may be associated with the activation of other mechanisms of cell cycle arrest in the G₀/G₁ phase.

CONCLUSIONS: Heterogeneous effect of the cytostatic agent dacarbazine on melanoma cells was revealed. For the SK-MEL-2 cell line, dacarbazine induces the release of senescence associated secretory phenotype by inhibiting exosomal production of miR-155-5p, which activates the p53 oncosuppressor, which was not observed in the BRO line.

Keywords

melanoma / microRNAs / exosomes / p53 / cellular senescence / miR-155-5p

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Funding

Российский научный фондRussian Science Foundation(19-15-00110)

RIGHTS & PERMISSIONS

Dashkova D.A., Esimbekova A.R., Kotova K.V., Ruksha T.G.