Cargando…

Interplay Between Mitophagy and Apoptosis Defines a Cell Fate Upon Co-treatment of Breast Cancer Cells With a Recombinant Fragment of Human κ-Casein and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

A recombinant fragment of human κ-Casein, termed RL2, induces cell death of breast cancer cells; however, molecular mechanisms of RL2-mediated cell death have remained largely unknown. In the current study, we have decoded the molecular mechanism of the RL2-mediated cell death and found that RL2 act...

Descripción completa

Detalles Bibliográficos
Autores principales: Wohlfromm, Fabian, Richter, Max, Otrin, Lado, Seyrek, Kamil, Vidaković-Koch, Tanja, Kuligina, Elena, Richter, Vladimir, Koval, Olga, Lavrik, Inna N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849764/
https://www.ncbi.nlm.nih.gov/pubmed/33537307
http://dx.doi.org/10.3389/fcell.2020.617762
_version_ 1783645357949845504
author Wohlfromm, Fabian
Richter, Max
Otrin, Lado
Seyrek, Kamil
Vidaković-Koch, Tanja
Kuligina, Elena
Richter, Vladimir
Koval, Olga
Lavrik, Inna N.
author_facet Wohlfromm, Fabian
Richter, Max
Otrin, Lado
Seyrek, Kamil
Vidaković-Koch, Tanja
Kuligina, Elena
Richter, Vladimir
Koval, Olga
Lavrik, Inna N.
author_sort Wohlfromm, Fabian
collection PubMed
description A recombinant fragment of human κ-Casein, termed RL2, induces cell death of breast cancer cells; however, molecular mechanisms of RL2-mediated cell death have remained largely unknown. In the current study, we have decoded the molecular mechanism of the RL2-mediated cell death and found that RL2 acts via the induction of mitophagy. This was monitored by the loss of adenosine triphosphate production, LC3B-II generation, and upregulation of BNIP3 and BNIP3L/NIX, as well as phosphatase and tensin homolog-induced kinase 1. Moreover, we have analyzed the cross talk of this pathway with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis upon combinatorial treatment with RL2 and TRAIL. Strikingly, we found two opposite effects of this co-treatment. RL2 had inhibitory effects on TRAIL-induced cell death upon short-term co-stimulation. In particular, RL2 treatment blocked TRAIL-mediated caspase activation, cell viability loss, and apoptosis, which was mediated via the downregulation of the core proapoptotic regulators. Contrary to short-term co-treatment, upon long-term co-stimulation, RL2 sensitized the cells toward TRAIL-induced cell death; the latter observation provides the basis for the development of therapeutic approaches in breast cancer cells. Collectively, our findings have important implications for cancer therapy and reveal the molecular switches of the cross talk between RL2-induced mitophagy and TRAIL-mediated apoptosis.
format Online
Article
Text
id pubmed-7849764
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-78497642021-02-02 Interplay Between Mitophagy and Apoptosis Defines a Cell Fate Upon Co-treatment of Breast Cancer Cells With a Recombinant Fragment of Human κ-Casein and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Wohlfromm, Fabian Richter, Max Otrin, Lado Seyrek, Kamil Vidaković-Koch, Tanja Kuligina, Elena Richter, Vladimir Koval, Olga Lavrik, Inna N. Front Cell Dev Biol Cell and Developmental Biology A recombinant fragment of human κ-Casein, termed RL2, induces cell death of breast cancer cells; however, molecular mechanisms of RL2-mediated cell death have remained largely unknown. In the current study, we have decoded the molecular mechanism of the RL2-mediated cell death and found that RL2 acts via the induction of mitophagy. This was monitored by the loss of adenosine triphosphate production, LC3B-II generation, and upregulation of BNIP3 and BNIP3L/NIX, as well as phosphatase and tensin homolog-induced kinase 1. Moreover, we have analyzed the cross talk of this pathway with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis upon combinatorial treatment with RL2 and TRAIL. Strikingly, we found two opposite effects of this co-treatment. RL2 had inhibitory effects on TRAIL-induced cell death upon short-term co-stimulation. In particular, RL2 treatment blocked TRAIL-mediated caspase activation, cell viability loss, and apoptosis, which was mediated via the downregulation of the core proapoptotic regulators. Contrary to short-term co-treatment, upon long-term co-stimulation, RL2 sensitized the cells toward TRAIL-induced cell death; the latter observation provides the basis for the development of therapeutic approaches in breast cancer cells. Collectively, our findings have important implications for cancer therapy and reveal the molecular switches of the cross talk between RL2-induced mitophagy and TRAIL-mediated apoptosis. Frontiers Media S.A. 2021-01-18 /pmc/articles/PMC7849764/ /pubmed/33537307 http://dx.doi.org/10.3389/fcell.2020.617762 Text en Copyright © 2021 Wohlfromm, Richter, Otrin, Seyrek, Vidaković-Koch, Kuligina, Richter, Koval and Lavrik. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Wohlfromm, Fabian
Richter, Max
Otrin, Lado
Seyrek, Kamil
Vidaković-Koch, Tanja
Kuligina, Elena
Richter, Vladimir
Koval, Olga
Lavrik, Inna N.
Interplay Between Mitophagy and Apoptosis Defines a Cell Fate Upon Co-treatment of Breast Cancer Cells With a Recombinant Fragment of Human κ-Casein and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
title Interplay Between Mitophagy and Apoptosis Defines a Cell Fate Upon Co-treatment of Breast Cancer Cells With a Recombinant Fragment of Human κ-Casein and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
title_full Interplay Between Mitophagy and Apoptosis Defines a Cell Fate Upon Co-treatment of Breast Cancer Cells With a Recombinant Fragment of Human κ-Casein and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
title_fullStr Interplay Between Mitophagy and Apoptosis Defines a Cell Fate Upon Co-treatment of Breast Cancer Cells With a Recombinant Fragment of Human κ-Casein and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
title_full_unstemmed Interplay Between Mitophagy and Apoptosis Defines a Cell Fate Upon Co-treatment of Breast Cancer Cells With a Recombinant Fragment of Human κ-Casein and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
title_short Interplay Between Mitophagy and Apoptosis Defines a Cell Fate Upon Co-treatment of Breast Cancer Cells With a Recombinant Fragment of Human κ-Casein and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
title_sort interplay between mitophagy and apoptosis defines a cell fate upon co-treatment of breast cancer cells with a recombinant fragment of human κ-casein and tumor necrosis factor-related apoptosis-inducing ligand
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849764/
https://www.ncbi.nlm.nih.gov/pubmed/33537307
http://dx.doi.org/10.3389/fcell.2020.617762
work_keys_str_mv AT wohlfrommfabian interplaybetweenmitophagyandapoptosisdefinesacellfateuponcotreatmentofbreastcancercellswitharecombinantfragmentofhumankcaseinandtumornecrosisfactorrelatedapoptosisinducingligand
AT richtermax interplaybetweenmitophagyandapoptosisdefinesacellfateuponcotreatmentofbreastcancercellswitharecombinantfragmentofhumankcaseinandtumornecrosisfactorrelatedapoptosisinducingligand
AT otrinlado interplaybetweenmitophagyandapoptosisdefinesacellfateuponcotreatmentofbreastcancercellswitharecombinantfragmentofhumankcaseinandtumornecrosisfactorrelatedapoptosisinducingligand
AT seyrekkamil interplaybetweenmitophagyandapoptosisdefinesacellfateuponcotreatmentofbreastcancercellswitharecombinantfragmentofhumankcaseinandtumornecrosisfactorrelatedapoptosisinducingligand
AT vidakovickochtanja interplaybetweenmitophagyandapoptosisdefinesacellfateuponcotreatmentofbreastcancercellswitharecombinantfragmentofhumankcaseinandtumornecrosisfactorrelatedapoptosisinducingligand
AT kuliginaelena interplaybetweenmitophagyandapoptosisdefinesacellfateuponcotreatmentofbreastcancercellswitharecombinantfragmentofhumankcaseinandtumornecrosisfactorrelatedapoptosisinducingligand
AT richtervladimir interplaybetweenmitophagyandapoptosisdefinesacellfateuponcotreatmentofbreastcancercellswitharecombinantfragmentofhumankcaseinandtumornecrosisfactorrelatedapoptosisinducingligand
AT kovalolga interplaybetweenmitophagyandapoptosisdefinesacellfateuponcotreatmentofbreastcancercellswitharecombinantfragmentofhumankcaseinandtumornecrosisfactorrelatedapoptosisinducingligand
AT lavrikinnan interplaybetweenmitophagyandapoptosisdefinesacellfateuponcotreatmentofbreastcancercellswitharecombinantfragmentofhumankcaseinandtumornecrosisfactorrelatedapoptosisinducingligand