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19 pages, 4161 KiB

Open AccessArticle

Macrophage-like THP-1 Cells Derived from High-Density Cell Culture Are Resistant to TRAIL-Induced Cell Death via Down-Regulation of Death-Receptors DR4 and DR5

by Yana Vladimirovna Lomovskaya, Margarita Igorevna Kobyakova, Anatoly Sergeevich Senotov, Alexey Igorevich Lomovsky, Vladislav Valentinovich Minaychev, Irina Sergeevna Fadeeva, Daria Yuryevna Shtatnova, Kirill Sergeevich Krasnov, Alena Igorevna Zvyagina, Vladimir Semenovich Akatov and Roman Sergeevich Fadeev

Biomolecules 2022, 12(2), 150; https://doi.org/10.3390/biom12020150 - 18 Jan 2022

Cited by 12 | Viewed by 5422

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a highly selective and promising anticancer agent due to its specific apoptosis-inducing effect on tumor cells, rather than most normal cells. TRAIL is currently under investigation for use in the treatment of leukemia. However, the resistance [...] Read more.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a highly selective and promising anticancer agent due to its specific apoptosis-inducing effect on tumor cells, rather than most normal cells. TRAIL is currently under investigation for use in the treatment of leukemia. However, the resistance of leukemic cells to TRAIL-induced apoptosis may limit its efficacy. The mechanisms of leukemic cell resistance to antitumor immunity remains a topical issue. In this work, we have found an increase in the resistance to TRAIL-induced cell death in human leukemia THP-1 cells, which was caused by differentiation into a macrophage-like phenotype in high-density culture in vitro. Stressful conditions, manifested by the inhibition of cell growth and the activation of cell death in high-density culture of THP-1 cells, induced the appearance of cells adhered to culture dishes. The THP-1ad cell line was derived by selection of these adhered cells. The genetic study, using STR and aCGH assays, has shown that THP-1ad cells were derived from THP-1 cells due to mutagenesis. The THP-1ad cells possessed high proliferative potential and a macrophage-like immunophenotype. The adhesion of THP-1ad cells to the extracellular matrix was mediated by αVβ5 integrin. The cytokine production, as well as the rise of intracellular ROS and NO activities by LPS in THP-1ad cell culture, were characteristic of macrophage-like cells. The THP-1ad cells were found to appear to increase in resistance to TRAIL-induced cell death in comparison with THP-1 cells. The mechanism of the increase in TRAIL-resistance can be related to a decrease in the expression of death receptors DR4 and DR5 on the THP-1ad cells. Thus, the macrophage-like phenotype formation with the maintenance of a high proliferative potential of leukemic cells, caused by stress conditions in high-density cell cultures in vitro, can induce an increase in resistance to TRAIL-induced cell death due to the loss of DR4 and DR5 receptors. The possible realization of these events in vivo may be the reason for tumor progression. Full article

(This article belongs to the Special Issue Death Receptors: New Opportunities in Cancer Therapy)

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Review

Jump to: Research

17 pages, 1458 KiB

Open AccessReview

Overcoming TRAIL Resistance for Glioblastoma Treatment

by Longfei Deng, Xuan Zhai, Ping Liang and Hongjuan Cui

Biomolecules 2021, 11(4), 572; https://doi.org/10.3390/biom11040572 - 14 Apr 2021

Cited by 17 | Viewed by 3563

Abstract

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows a promising therapeutic potential in cancer treatment as it exclusively causes apoptosis in a broad spectrum of cancer cells through triggering the extrinsic apoptosis pathway via binding to cognate death receptors, with negligible toxicity [...] Read more.

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows a promising therapeutic potential in cancer treatment as it exclusively causes apoptosis in a broad spectrum of cancer cells through triggering the extrinsic apoptosis pathway via binding to cognate death receptors, with negligible toxicity in normal cells. However, most cancers, including glioblastoma multiforme (GBM), display TRAIL resistance, hindering its application in clinical practice. Recent studies have unraveled novel mechanisms in regulating TRAIL-induced apoptosis in GBM and sought effective combinatorial modalities to sensitize GBM to TRAIL treatment, establishing pre-clinical foundations and the reasonable expectation that the TRAIL/TRAIL death receptor axis could be harnessed to treat GBM. In this review, we will revisit the status quo of the mechanisms of TRAIL resistance and emerging strategies for sensitizing GBM to TRAIL-induced apoptosis and also discuss opportunities of TRAIL-based combinatorial therapies in future clinical use for GBM treatment. Full article

(This article belongs to the Special Issue Death Receptors: New Opportunities in Cancer Therapy)

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16 pages, 1659 KiB

Open AccessReview

Regulation of Cancer Metastasis by TRAIL/Death Receptor Signaling

by You-Take Oh and Shi-Yong Sun

Biomolecules 2021, 11(4), 499; https://doi.org/10.3390/biom11040499 - 26 Mar 2021

Cited by 25 | Viewed by 3624

Abstract

Death ligands such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; TNFSF10) and their corresponding death receptors (e.g., DR5) not only initiate apoptosis through activation of the extrinsic apoptotic pathway but also exert non-apoptotic biological functions such as regulation of inflammation and cancer metastasis. [...] Read more.

Death ligands such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; TNFSF10) and their corresponding death receptors (e.g., DR5) not only initiate apoptosis through activation of the extrinsic apoptotic pathway but also exert non-apoptotic biological functions such as regulation of inflammation and cancer metastasis. The involvement of the TRAIL/death receptor signaling pathway in the regulation of cancer invasion and metastasis is complex as both positive and negative roles have been reported. The underlying molecular mechanisms are even more complicated. This review will focus on discussing current knowledge in our understanding of the involvement of TRAIL/death receptor-mediated signaling in the regulation of cancer cell invasion and metastasis. Full article

(This article belongs to the Special Issue Death Receptors: New Opportunities in Cancer Therapy)

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