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Effect of Sodium Butyrate on Proliferative Signaling Cascades in Sensitive and Resistant to Histone Deacetylase Inhibitors Cells

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Abstract

To establish the mechanisms of transformed cells resistance to the histone deacetylase inhibitors (HDACi), we compared the changes of the main proliferative signaling cascades activities in cells that are sensitive or resistant to HDACi-induced apoptosis. We showed that PKB/Akt kinase was constitutively activated in cells sensitive to HDAC inhibitor sodium butyrate induced apoptosis, while in sodium butyrate resistant cells, PKB/Akt kinase phosphorylation decreased under the sodium butyrate treatment. Nonlinear time-dependent dynamics of the ERK kinase activity was shown. Phosphorylation of ERK kinase increased in the first 24 hours of the HDACi sodium butyrate treatment, followed by ERK activity decrease in resistant cells. Whereas in apoptotic cells, an inverse time-dependent dynamics of ERK activity was observed. It has been shown that resistance to HDACi can be overcome by inhibiting the MEK/ERK pathway: sodium butyrate in combination with the inhibitor of the MEK/ERK pathway PD098059 induced apoptosis in resistant cells within 48 h. The study of the Wnt/β-catenin signaling cascade showed that the accumulation and transcriptional activation of β-catenin occurs only in cells resistant to HDACi-induced apoptosis. Whilst the amount and activity of β-catenin did not change under sodium butyrate treatment in the HDACi-sensitive cells. Thus, our results indicate that the β-catenin activity modulation is one of the reasons for cancer cells resistance to HDAC inhibitor’s pro-apoptotic action; the increased activity of the PI3K/PKB/Akt and MEK/ERK kinase pathways is a prerequisite for the most effective antiproliferative action of HDAC inhibitors.

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Funding

This work was supported by the Committee for Science and Higher School at the Government of St. Petersburg and by the Foundation of the Director of the Institute of Cytology of the Russian Academy of Sciences.

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    O. O. Gnedina & M. V. Igotti

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Accepted abbreviations: HDAC—histone deacetylases; HDACi— HDAC inhibitor; SA β-Gal—senescence-associated beta-galactosidase.

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Gnedina, O.O., Igotti, M.V. Effect of Sodium Butyrate on Proliferative Signaling Cascades in Sensitive and Resistant to Histone Deacetylase Inhibitors Cells. Cell Tiss. Biol. 15, 236–247 (2021). https://doi.org/10.1134/S1990519X21030020

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