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ONC201-Induced Mitochondrial Dysfunction, Senescence-like Phenotype, and Sensitization of Cultured BT474 Human Breast Cancer Cells to TRAIL

ONC201, the anticancer drug, targets and activates mitochondrial ATP-dependent caseinolytic peptidase P (ClpP), a serine protease located in the mitochondrial matrix. Given the promise of ONC201 in cancer treatment, we evaluated its effects on the breast ductal carcinoma cell line (BT474). We showed...

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Autores principales: Mishukov, Artem, Odinokova, Irina, Mndlyan, Ekaterina, Kobyakova, Margarita, Abdullaev, Serazhutdin, Zhalimov, Vitaly, Glukhova, Xenia, Galat, Vasiliy, Galat, Yekaterina, Senotov, Anatoly, Fadeev, Roman, Artykov, Artem, Gasparian, Marine E., Solovieva, Marina, Beletsky, Igor, Holmuhamedov, Ekhson
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779726/
https://www.ncbi.nlm.nih.gov/pubmed/36555190
http://dx.doi.org/10.3390/ijms232415551
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author Mishukov, Artem
Odinokova, Irina
Mndlyan, Ekaterina
Kobyakova, Margarita
Abdullaev, Serazhutdin
Zhalimov, Vitaly
Glukhova, Xenia
Galat, Vasiliy
Galat, Yekaterina
Senotov, Anatoly
Fadeev, Roman
Artykov, Artem
Gasparian, Marine E.
Solovieva, Marina
Beletsky, Igor
Holmuhamedov, Ekhson
author_facet Mishukov, Artem
Odinokova, Irina
Mndlyan, Ekaterina
Kobyakova, Margarita
Abdullaev, Serazhutdin
Zhalimov, Vitaly
Glukhova, Xenia
Galat, Vasiliy
Galat, Yekaterina
Senotov, Anatoly
Fadeev, Roman
Artykov, Artem
Gasparian, Marine E.
Solovieva, Marina
Beletsky, Igor
Holmuhamedov, Ekhson
author_sort Mishukov, Artem
collection PubMed
description ONC201, the anticancer drug, targets and activates mitochondrial ATP-dependent caseinolytic peptidase P (ClpP), a serine protease located in the mitochondrial matrix. Given the promise of ONC201 in cancer treatment, we evaluated its effects on the breast ductal carcinoma cell line (BT474). We showed that the transient single-dose treatment of BT474 cells by 10 µM ONC201 for a period of less than 48 h induced a reversible growth arrest and a transient activation of an integrated stress response indicated by an increased expression of CHOP, ATF4, and GDF-15, and a reduced number of mtDNA nucleoids. A prolonged exposure to the drug (>48 h), however, initiated an irreversible loss of mtDNA, persistent activation of integrated stress response proteins, as well as cell cycle arrest, inhibition of proliferation, and suppression of the intrinsic apoptosis pathway. Since Natural Killer (NK) cells are quickly gaining momentum in cellular anti-cancer therapies, we evaluated the effect of ONC201 on the activity of the peripheral blood derived NK cells. We showed that following the ONC 201 exposure BT474 cells demonstrated enhanced sensitivity toward human NK cells that mediated killing. Together our data revealed that the effects of a single dose of ONC201 are dependent on the duration of exposure, specifically, while short-term exposure led to reversible changes; long-term exposure resulted in irreversible transformation of cells associated with the senescent phenotype. Our data further demonstrated that when used in combination with NK cells, ONC201 created a synergistic anti-cancer effect, thus suggesting its possible benefit in NK-cell based cellular immunotherapies for cancer treatment.
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spelling pubmed-97797262022-12-23 ONC201-Induced Mitochondrial Dysfunction, Senescence-like Phenotype, and Sensitization of Cultured BT474 Human Breast Cancer Cells to TRAIL Mishukov, Artem Odinokova, Irina Mndlyan, Ekaterina Kobyakova, Margarita Abdullaev, Serazhutdin Zhalimov, Vitaly Glukhova, Xenia Galat, Vasiliy Galat, Yekaterina Senotov, Anatoly Fadeev, Roman Artykov, Artem Gasparian, Marine E. Solovieva, Marina Beletsky, Igor Holmuhamedov, Ekhson Int J Mol Sci Article ONC201, the anticancer drug, targets and activates mitochondrial ATP-dependent caseinolytic peptidase P (ClpP), a serine protease located in the mitochondrial matrix. Given the promise of ONC201 in cancer treatment, we evaluated its effects on the breast ductal carcinoma cell line (BT474). We showed that the transient single-dose treatment of BT474 cells by 10 µM ONC201 for a period of less than 48 h induced a reversible growth arrest and a transient activation of an integrated stress response indicated by an increased expression of CHOP, ATF4, and GDF-15, and a reduced number of mtDNA nucleoids. A prolonged exposure to the drug (>48 h), however, initiated an irreversible loss of mtDNA, persistent activation of integrated stress response proteins, as well as cell cycle arrest, inhibition of proliferation, and suppression of the intrinsic apoptosis pathway. Since Natural Killer (NK) cells are quickly gaining momentum in cellular anti-cancer therapies, we evaluated the effect of ONC201 on the activity of the peripheral blood derived NK cells. We showed that following the ONC 201 exposure BT474 cells demonstrated enhanced sensitivity toward human NK cells that mediated killing. Together our data revealed that the effects of a single dose of ONC201 are dependent on the duration of exposure, specifically, while short-term exposure led to reversible changes; long-term exposure resulted in irreversible transformation of cells associated with the senescent phenotype. Our data further demonstrated that when used in combination with NK cells, ONC201 created a synergistic anti-cancer effect, thus suggesting its possible benefit in NK-cell based cellular immunotherapies for cancer treatment. MDPI 2022-12-08 /pmc/articles/PMC9779726/ /pubmed/36555190 http://dx.doi.org/10.3390/ijms232415551 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mishukov, Artem
Odinokova, Irina
Mndlyan, Ekaterina
Kobyakova, Margarita
Abdullaev, Serazhutdin
Zhalimov, Vitaly
Glukhova, Xenia
Galat, Vasiliy
Galat, Yekaterina
Senotov, Anatoly
Fadeev, Roman
Artykov, Artem
Gasparian, Marine E.
Solovieva, Marina
Beletsky, Igor
Holmuhamedov, Ekhson
ONC201-Induced Mitochondrial Dysfunction, Senescence-like Phenotype, and Sensitization of Cultured BT474 Human Breast Cancer Cells to TRAIL
title ONC201-Induced Mitochondrial Dysfunction, Senescence-like Phenotype, and Sensitization of Cultured BT474 Human Breast Cancer Cells to TRAIL
title_full ONC201-Induced Mitochondrial Dysfunction, Senescence-like Phenotype, and Sensitization of Cultured BT474 Human Breast Cancer Cells to TRAIL
title_fullStr ONC201-Induced Mitochondrial Dysfunction, Senescence-like Phenotype, and Sensitization of Cultured BT474 Human Breast Cancer Cells to TRAIL
title_full_unstemmed ONC201-Induced Mitochondrial Dysfunction, Senescence-like Phenotype, and Sensitization of Cultured BT474 Human Breast Cancer Cells to TRAIL
title_short ONC201-Induced Mitochondrial Dysfunction, Senescence-like Phenotype, and Sensitization of Cultured BT474 Human Breast Cancer Cells to TRAIL
title_sort onc201-induced mitochondrial dysfunction, senescence-like phenotype, and sensitization of cultured bt474 human breast cancer cells to trail
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779726/
https://www.ncbi.nlm.nih.gov/pubmed/36555190
http://dx.doi.org/10.3390/ijms232415551
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