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ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics

BACKGROUND: Triple negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its aggressive behavior and frequent development of resistance to chemotherapy. Although natural killer (NK) cell-based immunotherapy is a promising strategy for overcoming barriers to cancer treatmen...

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Autores principales: Park, Joo Dong, Kim, Kwang-Soo, Choi, Seung Hee, Jo, Gae Hoon, Choi, Jin-Ho, Park, Si-Won, Ko, Eun-Su, Lee, Minwook, Lee, Dae-Keum, Jang, Hye Jung, Hwang, Sohyun, Jung, Hae-Yun, Park, Kyung-Soon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305827/
https://www.ncbi.nlm.nih.gov/pubmed/35858708
http://dx.doi.org/10.1136/jitc-2022-004825
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author Park, Joo Dong
Kim, Kwang-Soo
Choi, Seung Hee
Jo, Gae Hoon
Choi, Jin-Ho
Park, Si-Won
Ko, Eun-Su
Lee, Minwook
Lee, Dae-Keum
Jang, Hye Jung
Hwang, Sohyun
Jung, Hae-Yun
Park, Kyung-Soon
author_facet Park, Joo Dong
Kim, Kwang-Soo
Choi, Seung Hee
Jo, Gae Hoon
Choi, Jin-Ho
Park, Si-Won
Ko, Eun-Su
Lee, Minwook
Lee, Dae-Keum
Jang, Hye Jung
Hwang, Sohyun
Jung, Hae-Yun
Park, Kyung-Soon
author_sort Park, Joo Dong
collection PubMed
description BACKGROUND: Triple negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its aggressive behavior and frequent development of resistance to chemotherapy. Although natural killer (NK) cell-based immunotherapy is a promising strategy for overcoming barriers to cancer treatment, the therapeutic efficacy of NK cells against TNBC is below expectations. E26 transformation-specific transcription factor ELK3 (ELK3) is highly expressed in TNBCs and functions as a master regulator of the epithelial-mesenchymal transition. METHODS: Two representative human TNBC cell lines, MDA-MB231 and Hs578T, were exposed to ELK3-targeting shRNA or an ELK3-expressing plasmid to modulate ELK3 expression. The downstream target genes of ELK3 were identified using a combined approach comprising gene expression profiling and molecular analysis. The role of ELK3 in determining the immunosensitivity of TNBC to NK cells was investigated in terms of mitochondrial fission–fusion transition and reactive oxygen species concentration both in vitro and in vivo. RESULTS: ELK3-dependent mitochondrial fission–fusion status was linked to the mitochondrial superoxide concentration in TNBCs and was a main determinant of NK cell-mediated immune responses. We identified mitochondrial dynamics proteins of 51 (Mid51), a major mediator of mitochondrial fission, as a direct downstream target of ELK3 in TNBCs. Also, we demonstrated that expression of ELK3 correlated inversely with that of Mid51, and that the ELK3-Mid51 axis is associated directly with the status of mitochondrial dynamics. METABRIC analysis revealed that the ELK3-Mid51 axis has a direct effect on the immune score and survival of patients with TNBC. CONCLUSIONS: Taken together, the data suggest that NK cell responses to TNBC are linked directly to ELK3 expression levels, shedding new light on strategies to improve the efficacy of NK cell-based immunotherapy of TNBC.
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spelling pubmed-93058272022-08-11 ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics Park, Joo Dong Kim, Kwang-Soo Choi, Seung Hee Jo, Gae Hoon Choi, Jin-Ho Park, Si-Won Ko, Eun-Su Lee, Minwook Lee, Dae-Keum Jang, Hye Jung Hwang, Sohyun Jung, Hae-Yun Park, Kyung-Soon J Immunother Cancer Basic Tumor Immunology BACKGROUND: Triple negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its aggressive behavior and frequent development of resistance to chemotherapy. Although natural killer (NK) cell-based immunotherapy is a promising strategy for overcoming barriers to cancer treatment, the therapeutic efficacy of NK cells against TNBC is below expectations. E26 transformation-specific transcription factor ELK3 (ELK3) is highly expressed in TNBCs and functions as a master regulator of the epithelial-mesenchymal transition. METHODS: Two representative human TNBC cell lines, MDA-MB231 and Hs578T, were exposed to ELK3-targeting shRNA or an ELK3-expressing plasmid to modulate ELK3 expression. The downstream target genes of ELK3 were identified using a combined approach comprising gene expression profiling and molecular analysis. The role of ELK3 in determining the immunosensitivity of TNBC to NK cells was investigated in terms of mitochondrial fission–fusion transition and reactive oxygen species concentration both in vitro and in vivo. RESULTS: ELK3-dependent mitochondrial fission–fusion status was linked to the mitochondrial superoxide concentration in TNBCs and was a main determinant of NK cell-mediated immune responses. We identified mitochondrial dynamics proteins of 51 (Mid51), a major mediator of mitochondrial fission, as a direct downstream target of ELK3 in TNBCs. Also, we demonstrated that expression of ELK3 correlated inversely with that of Mid51, and that the ELK3-Mid51 axis is associated directly with the status of mitochondrial dynamics. METABRIC analysis revealed that the ELK3-Mid51 axis has a direct effect on the immune score and survival of patients with TNBC. CONCLUSIONS: Taken together, the data suggest that NK cell responses to TNBC are linked directly to ELK3 expression levels, shedding new light on strategies to improve the efficacy of NK cell-based immunotherapy of TNBC. BMJ Publishing Group 2022-07-20 /pmc/articles/PMC9305827/ /pubmed/35858708 http://dx.doi.org/10.1136/jitc-2022-004825 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Basic Tumor Immunology
Park, Joo Dong
Kim, Kwang-Soo
Choi, Seung Hee
Jo, Gae Hoon
Choi, Jin-Ho
Park, Si-Won
Ko, Eun-Su
Lee, Minwook
Lee, Dae-Keum
Jang, Hye Jung
Hwang, Sohyun
Jung, Hae-Yun
Park, Kyung-Soon
ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics
title ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics
title_full ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics
title_fullStr ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics
title_full_unstemmed ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics
title_short ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics
title_sort elk3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics
topic Basic Tumor Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305827/
https://www.ncbi.nlm.nih.gov/pubmed/35858708
http://dx.doi.org/10.1136/jitc-2022-004825
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