Pro-Inflammatory Activation Suppresses TRAIL-induced Apoptosis of Acute Myeloid Leukemia Cells

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Margarita I. Kobyakova^1,2,a*, Anatoly S. Senotov¹, Kirill S. Krasnov¹, Yana V. Lomovskaya¹, Irina V. Odinokova¹, Anastasia A. Kolotova¹, Artem M. Ermakov¹, Alena I. Zvyagina¹, Irina S. Fadeeva¹, Elena I. Fetisova¹, Vladimir S. Akatov¹, and Roman S. Fadeev¹

¹Institute of Theoretical and Experimental Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

²Institute of Clinical and Experimental Lymphology, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630060 Novosibirsk, Russia

Received October 9, 2023; Revised November 17, 2023; Accepted December 12, 2023

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising agent for treatment of AML due to its specific apoptosis-inducing effect on tumor cells but not normal cells. However, emergence of resistance to TRAIL in the AML cells limits its potential as an antileukemic agent. Previously, we revealed increase in the resistance of the human AML THP-1 cells to the TRAIL-induced death during their LPS-dependent proinflammatory activation and in the in vitro model of LPS-independent proinflammatory activation – in a long-term high-density cell culture. In this study, we investigated mechanisms of this phenomenon using Western blot analysis, caspase 3 enzymatic activity analysis, quantitative reverse transcription-PCR, and flow cytometry. The results showed that the increased resistance to the TRAIL-induced cell death of AML THP-1 cells during their pro-inflammatory activation is associated with the decrease in the surface expression of the proapoptotic receptors TRAIL-R1/DR4 and TRAIL-R2/DR5, as well as with the increased content of members of the IAPs family – Livin and cIAP2. The results of this article open up new insights into the role of inflammation in formation of the resistance of AML cells to the action of mediators of antitumor immunity, in particular TRAIL.

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KEY WORDS: acute myeloid leukemia, resistance, pro-inflammatory cell activation, TRAIL-induced cell death

DOI: 10.1134/S0006297924030040

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